1-(1,2-Disubstituted piperidinyl)-4-substituted piperazine derivatives

ABSTRACT

This invention concerns the compounds of formula                    
     the N-oxide forms, the pharmaceutically acceptable addition salts and the stereoisomeric forms thereof, as substance-P antagonists; their preparation, compositions containing them and their use as a medicine.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of international applicationPCT/EP96/04660 filed Oct. 25, 1996, which designated the United Statesand is now abandoned.

This invention concerns 1-(1,2-disubstituted piperidinyl)-4-substitutedpiperazine derivatives having tachykinin antagonistic activity, inparticular substance P antagonistic activity, and their preparation, itfurther relates to compositions comprising them, as well as their use asa medicine.

Substance P is a naturally occurring neuropeptide of the tachykininfamily. There are ample studies showing that substance P and othertachykinins are involved in a variety of biological actions, andtherefore, play an essential role in various disorders (Regoli et al.,Pharmacological Reviews 46(4), 1994, p: 551-599, “Receptors andAntagonists for Substance P and Related Peptides”). The development oftachykinin antagonists has led to date to a series of peptide compoundsof which might be anticipated that they are metabolically too labile tobe employed as pharmaceutically active substances (Longmore J. et al.,DN&P 8(1), February 1995, p. 5-23. “Neurokinin Receptors”). The presentinvention concerns nonpeptide tachykinin antagonists, in particularnonpeptide substance-P antagonists, which in general are metabolicallymore stable, and hence, may be more appropriate as pharmaceuticallyactive substances.

Several nonpeptide tachykinin antagonists are disclosed in the art. Forinstance, EP-0,532,456-A, published on Mar. 17, 1993 by Ciba-GeigyCorp., discloses 1-acylpiperidine compounds, in particular2-arylalkyl-1-arylcarbonyl-4-piperidinamine derivatives, and their useas substance-P antagonists. EP-0,655,442-A published on May 31, 1995 byFujisawa Pharmaceutical Co. Ltd., discloses piperazine derivativeshaving tachykinin antagonistic activity.

The present compounds differ therefrom in that they invariably contain a4-substituted-(piperazine or homopiperazine)-moiety in the 4-position ofa piperidine- or homopiperidine group or in the 3-position of apyrrolidine group, and by their favourable farmacological properties.

The present invention concerns compounds of formula

the N-oxide forms, the pharmaceutically acceptable addition salts andthe stereochemically isomeric forms thereof,

wherein

n is 0, 1 or 2;

m is 1 or 2, provided that if m is 2, then n is 1;

p is 1 or 2;

═Q is ═) or ═NR³;

X is a convalent bond or a bivalent radical of formula —O—, —S—, —NR³—;

R¹ is Ar¹, Ar¹C₁₋₆alkyl or di(Ar¹)C₁₋₆alkyl, wherein each C₁₋₆alkylgroup is optionally substituted with hydroxy, C₁₋₄alkyloxy, oxo or aketalized oxo substituent of formula —O—CH₂—CH₂—O— or —O—CH₂—CH₂—CH₂—O—;

R² is Ar², Ar²C₁₋₆alkyl, Het¹ or Het¹C₁₋₆alkyl;

R³ is hydrogen or C₁₋₆alkyl;

L is hydrogen, Ar³; C₁₋₆alkyl; C₁₋₆alkyl substituted with 1 or 2substituents selected from hydroxy, C₁₋₆alkyloxy, Ar³, Ar³C₁₋₆alkyloxyand Het²; C₃₋₆alkenyl; Ar³C₃₋₆alkenyl; di(Ar³)C₃₋₆alkenyl or a radicalof formula

wherein each q independently is 2, 3 or 4;

each r is 0, 1, 2, 3 or 4;

each Y¹ independently is a covalent bond, —O— or NR³;

Y² is a covalent bond, C₁₋₄alkanediyl or —C₁₋₄alkylNR³—;

each —A═B— independently is a bivalent radical of formula —CH═CH—,—N═CH— or —CH═N—;

each R⁴ independently is hydrogen, C₁₋₆alkyl, Ar² or Ar²C₁₋₆ alkyl;

R⁵ is hydrogen, C₁₋₆alkyl or Ar³;

R⁶ is C₁₋₆alkyl, Ar³, Ar³C₁₋₆alkyl, di(Ar³)C₁₋₆alkyl, Ar³C₃₋₇cycloalkylor indolyl;

R⁷ is Ar³, Ar³C₁₋₆alkyl; di(Ar³)C₁₋₆alkyl; C₁₋₆alkyl; C₃₋₇cycloalkyl;C₃₋₇cycloalkyl substituted with Ar³; oxazolyl; oxazolyl substituted withhalo or C₁₋₆alkyl; thiazolyl; thiazolyl; thiazolyl substituted with haloor C₁₋₆alkyl; imidazolyl; imidazolyl substituted with Ar³, C₁₋₆alkyl,Ar³C₁₋₆alkyl or halo; indolinyl; indolinyl substituted with C₁₋₄alkyl;2,3,4-trihydroquinolinyl; pyrrolidinyl or furanyl;

each R⁸ independently is hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl or aradical of formula

—Alk—R¹¹   (b-1)

or

—Alk—Z—R¹²   (b-2);

wherein Alk is C₁₋₆alkanediyl;

Z is a bivalent radical of formula —O—, —S— or —NR³—;

R¹¹ is phenyl; phenyl substituted with 1 or 2 substituents selected fromhalo, C₁₋₆alkyl or C₁₋₆alkyloxy; furanyl; furanyl substituted with 1 or2 substituents selected from C₁₋₆alkyl or hydroxyC₁₋₆alkyl; thienyl;thienyl substituted with 1 or 2 substituents selected from halo orC₁₋₆alkyl; oxazolyl; oxazolyl substituted with 1 or 2 C₁₋₆alkylsubstituents, thiazolyl; thiazolyl substituted with 1 or 2 C₁₋₆alkylsubstituents; pyridinyl or pyridinyl substituted with 1 of 2 C₁₋₆alkylsubstituents;

R¹² is C₁₋₆alkyl or C₁₋₆alkyl substituted with hydroxy, carboxyl orC₁₋₆alkyloxycarbonyl;

Ar¹ is phenyl; phenyl substituted with 1,2 or 3 substituents eachindependently selected from halo, C₁₋₄alkyl, haloC₁₋₄alkyl, cyano,aminocarbonyl, C₁₋₄alkyloxy or haloC₁₋₄alkyloxy;

Ar² is naphtalenyl; phenyl; phenyl substituted with 1,2 or 3substituents each independently selected from hydroxy, halo, cyano,nitro, amino, mono- or di(C₁₋₄alkyl)amino, C₁₋₄alkyl, haloC₁₋₄alkyl,C₁₋₄alkyloxy, halo C₁₋₄alkyloxy, carboxyl, C₁₋₄alkyloxycarbonyl,aminocarbonyl and mono- or di(C₁₋₄alkyl) aminocarbonyl;

Ar³ is phenyl or phenyl substituted with 1, 2 or 3 substituents selectedfrom halo, hydroxy, amino, nitro, aminocarbonyl, C₁₋₆alkyl,haloC₁₋₆alkyl or C₁₋₆alkyloxy;

Het¹ is a monocyclic heterocycle selected from pyrrolyl, pyrazolyl,imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or abicyclic heterocycle selected from quinolinyl, quinoxalinyl, indolyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,benzisothiazolyl, benzofuranyl and benzothienyl; each monocyclic andbicyclic heterocycle may optionally be substituted on a carbon atom by 1of 2 substituents selected from halo, C₁₋₄alkyl or mono-, di ortri(halo)methyl; and

Het² is a heterocycle selected from 1,4-dihydro-5-oxo-tetrazol-1-yl,imidazo[1,2-a]-pyridinyl, oxazolyl or imidazolyl; each of saidheterocycles may be substituted with 1 or where possible 2 substituentsselected from C₁₋₄alkyl and Ar³.

The heterocycles in the definition of Het¹ are preferably connected tothe rest of the molecule, i.e. X, —C(═Q)— or C₁₋₆alkyl, by a carbonatom.

As used in the foregoing definitions and hereinafter halo is generic tofluoro, chloro, bomo and iodo; C₂₋₄alkyl defines straight and branchedchain saturated hydrocarbon radicals having from 2 to 4 carbon atomssuch as, for example, ethyl, propyl, butyl, 1-methylethyl,2-methylpropyl and the like; C₁₋₄alkyl is meant to include C₂₋₄alkyl andmethyl; C₁₋₅alkyl is meant to include C₁₋₄alkyl and the higherhomologues thereof having 5 carbon atoms such as, for example, pentyl,2-methylbutyl and the like; C₁₋₆alkyl is meant to include C₁₋₅alkyl andthe higher homologues thereof having 6 carbon atoms such as for example,hexyl, 2-methylpentyl and the like; C₁₋₄alkanediyl defines bivalentstraight and branched chain saturated hydrocarbon radicals having from 1to 4 carbon atoms such as, for example, methylene, 1,2-ethanediyl,1,3-propanediyl, 1,4-butanediyl, and the like; C₁₋₆alkanediyl is meantto include C₁₋₄alkanediyl and the higher homologues thereof having form5 to 6 carbon atoms such as for example, 1,5-pentanediyl, 1,6-hexanediyland the like; C₃₋₆alkenyl defines straight and branched chainhydrocarbon radicals containing one double bond and having from 3 to 6carbon atoms such as, for example, 2-propentyl, 3-butenyl, 3-hexenyl andthe like; and the carbon of said C₃₋₆alkenyl connected to the nitrogenatom of the piperazine or homopiperazine preferably is saturated.

As used in the foregoing definitions and hereinafter, haloC₁₋₄alkyl isdefined as mono- or polyhalosubstituted C₁₋₄alkyl, in particularC₁₋₄alkyl substitutred with 1 to 6 halogen atoms, more in particulardifluoro- or trifluoromethyl.

The pharmaceutically acceptable addition salts as mentioned hereinaboveare meant to comprise the therapeutically active non-toxic acid additionsalt forms which the compounds of formula (I) are able to form. Saidsalts can conveniently be obtained by treating the base form of thecompounds of formula (I) with appropriate acids such as, for example,inorganic acids such as hydrohalic acids, e.g. hydrochloric orhydrobromic acid; sulfuric; nitric; phosphoric and the like acids; ororganic acids such as, for example, acetic, propanoic, hydroxyacetic,lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic,tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic,p-toluenesulfonic, cyclamic, salicyclic, p-aminosalicyclic, pamoic andthe like acids.

The pharmaceutically acceptable addition salts as mentioned hereinaboveare also meant to comprise the therapeutically active non-toxic base, inparticular, a metal or amine addition salt forms which the compounds offormula (I) are able to form. Said salts can conveniently be obtained bytreating the compounds of formula (I) containing acidic hydrogen atomswith appropriate organic and inorganic bases such as, for example, theammonium salts, the alkali and earth alkaline metal salts, e.g. thelithium, sodium, potassium, magnesium, calcium salts and the like, saltswith organic bases, e.g. the benzathine, N-methyl-D-glucamine,hydrabamine salts, and salts with amino acids such as, for example,arginine, lysine and the like.

Conversely said salt forms can be converted by treatment with anappropriate base or acid into the free acid or base form.

The term addition salt as used hereinablve also comprises the solvateswhich the compounds of formula (I) as well as the salts thereof, areable to form. Such solvates are for example hydrates, alcoholates andthe like.

For isolation and purification purposes, it is also possible to usepharmaceutically unacceptable salts. Only the pharmaceuticallyacceptable, non-toxic salts are used therapeutically and those salts aretherefore preferred.

The term “stereochemically isomeric forms” as used hereinbefore definesall the possible isomeric as well as conformational forms which thecompounds of formula (I) may possess. Unless otherwise mentioned orindicated, the chemical designation of compounds denotes the mixture,more in particular the recemic mixture, of all possible stereochemicallyand conformationally isomeric forms, said mixtures containing alldiastereomers, enantiomers and/or conformers of the basic molecularstructure. More in particular, stereogenic centers may have the R- orS-configuration; substituents on bivalent cyclic saturated radicals mayhave either the cis- or trans-configuration; >C═NR³ and C₃₋₆alkenylradicals may have the E- or Z-configuration. The compounds of formula(I) have at least two stereogenic centers; thus for compounds of whichthe actual stereochemical configuration is known, the relativestereodescriptors R* and S* may be used in accordance with the ChemicalAbstracts rules (Chemical Substance Name Selection Manual (CA), 1982Edition, Vol. III, Chapter 20). In those cases where the compounds offormula (I) were separated into its racemic cis and racemic transisomers, or in those cases where the racemic cis or racemic transisomerswere separated into its pure enantiomeric forms, the stereochemicallyisomeric form which was first isolated was designated as “A” and thesecond as “B”. All stereochemically isomeric forms of the compounds offormula (I) both in pure form or mixtures thereof are intended to beembraced within the scope of the present invention.

Some of the compounds of formula (I) may also exist in their tautomericform. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.For instance, compounds of formula (I) wherein L is a radical of formula(a-1) wherein R⁵ is hydrogen, or a radical of (a-2) or (a-3) wherein Y¹is —NH—, or a radical of formula (a-5) wherein R³ is hydrogen may existin their corresponding tautomeric form. Also compounds of formula (I)wherein X is —NH— and ═Q is ═O may exist in their correspondingtautomeric form.

The N-oxide forms of the compounds of formula (I) are meant to comprisethose compounds of formula (I) wherein one or several nitrogen atoms areoxidized to the so-called N-oxide, particularly those N-oxides whereinone or more of the piperazine-nitrogens are N-oxidized.

Whenever used hereinafter, the term “compounds of formula (I)” is meantto also include their N-oxide forms, their pharmaceutically acceptableaddition salts, and their stereochemically isomeric forms.

A special group of compounds are those compounds of formula (I) whereinL is hydrogen; C₁₋₆alkyl; C₁₋₆alkyl substituted with hydroxy;C₃₋₆alkenyl; Ar³; Ar³C₁₋₆alkyl; di(Ar³)C₁₋₆alkyl; Ar³C₃₋₆alkenyl;di(Ar³)C₁₋₆alkenyl; or a radical of formula (a-1), (a-2), (a-4) or (a-5)wherein

R⁷ is Ar³; Ar³C₁₋₆alkyl; di(Ar³)C₁₋₆alkyl; C₁₋₆alkyl; C₃₋₇cycloalkyl;C₃₋₇cycloalkyl substituted with Ar³; oxazolyl; oxazolyl substituted withhalo or C₁₋₆alkyl; thiazolyl; thiazolyl substituted with halo orC₁₋₆alkyl; imidazolyl; imidazolyl substituted with Ar³, C₁₋₆alkyl,Ar³C₁₋₆alkyl or halo; pyrrolidinyl or furanyl;

Ar³ is phenyl or phenyl substituted with 1, 2 or 3 substituents selectedfrom halo, hydroxy, amino, aminocarbonyl, C₁₋₆alkyl, haloC₁₋₆alkyl orC₁₋₆alkyloxy;

Het¹ is a monocyclic heterocycle selected from pyrrolyl, pyrazolyl,imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or abicyclic heterocycle selected from quinolinyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,benzofuranyl and benzothienyl; each monocyclic and bicyclic heterocyclemay optionally be substituted on a carbon atom by 1 to 2 substituentsselected from halo, C₁₋₄alkyl or mono-, di or tri(halo) methyl.

A first group of interesting compounds consists of those compounds offormula (I) wherein one or more of the following restrictions apply:

a) R¹ is Ar¹C₁₋₆alkyl; or

b) R² is Ar², Ar²C₁₋₆alkyl or Het¹; in particular, phenyl substitutedwith 1, 2 or 3 substituents each independently selected from halo,cyano, nitro, amino, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkyloxy andC₁₋₄alkyloxycarbonyl, more in particular, phenyl substituted with 2substituents selected from methyl and trifluoromethyl; or

c) n is 0 or 1, in particular n is 1; or

d) m is 1; or

e) p is 1 or 2, in particular p is 1; or

f) ═Q is ═O; or

g) X is a covalent bond, —O— or —NR³—, in particular a covalent bond.

A second group of interesting compounds consists of those compounds offormula (I) wherein L is hydrogen, Ar³; Ar³C₁₋₆alkyl; di(Ar³)C₁₋₆alkyl;Ar³C₃₋₆alkenyl; C₁₋₆alkyl substituted with hydroxy; or

a radical of formula (a-2) wherein

R⁴ is hydrogen or Ar²;

r is 0 or 1;

Y¹ is a covalent bond, —O— or —NR³—; and

R⁷ is Ar³, C₃₋₇cycloalkyl substituted with Ar³, di(Ar³) methyl,pyrrolidinyl or furanyl; or

a radical of formula (a-4) wherein

Y² a covalent bond or methylene;

—A═B— is —CH═CH— or —N═CH—; and

R⁸ hydrogen, a radical of formula (b-1) wherein R¹¹ is methylsubstituted oxazolyl, or a radical of formula (b-2) wherein Z is —O— andR¹² is C₁₋₆alkyl; or

a radical of formula (a-5) wherein

R⁴ is hydrogen;

q 2; and

R³ is hydrogen.

A third group of interesting compounds consists of those compounds offormula (I) wherein

q is 2 or 4;

—A═B— is —CH═CH— or —N═CH—;

R⁴ is hydrogen or Ar²;

R⁵ is hydrogen;

R⁶ is C₁₋₆alkyl or Ar³;

R⁷ is Ar³; di(Ar³)C₁₋₆alkyl; C₁₋₆alkyl; C₃₋₇cycloalkyl substituted withAr³; thiazolyl; imidazolyl substituted with C₁₋₆alkyl or Ar³C₁₋₆alkyl;indolinyl; indolinyl substituted with C₁₋₄alkyl;2,3,4-trihydroquinolinyl; pyrrolidinyl or furanyl;

Z is —O—;

R¹¹ is phenyl substituted with halo; oxazolyl substituted withC₁₋₆alkyl; or

R¹² is C₁₋₆alkyl.

Of special interest are those compounds of formula (I) wherein R¹ isAr¹C₁₋₆alkyl, R² is phenyl substituted with 2 substituents selected frommethyl or trifluoromethyl, X is a covalent bond and ═Q is ═O.

Further of special interest are those compounds of formula (I) wherein nand m are 1 and p is 1 or 2.

Particular compounds are those compounds of formula (I) wherein

R¹ is phenylmethyl;

R² is phenyl substituted with 2 substituents selected from methyl ortrifluoromethyl;

n, m and p are 1;

X is a covalent bond; and

═Q is ═O.

Also particular compounds are those compounds of formula (I) wherein Lis a radical of formula (a-2) wherein

R⁴ is hydrogen or phenyl;

r is 0 or 1;

Y¹ is a covalent bond, —O— or —NH—;

R⁷ is pyrrolidinyl; furanyl; 1-phenylcyclohexanyl; diphenylmethyl; orphenyl substituted with 1, 2 or 3 substituents each independentlyselected from methyl, methoxy or chloro.

Preferred compounds are those particular compounds that have a transconfiguration.

Other preferred compounds are those particular compounds that have a cisconfiguration.

Still other preferred compounds are those compounds of formula (I)wherein

R¹ is phenylmethyl;

R² is phenyl substituted with 2 substituents selected from methyl ortrifluoromethyl;

n, m and p are 1;

X is a covalent bond;

═Q is ═O;

L is a radical of formula (a-2) wherein

R⁴ is hydrogen;

r is 1;

Y¹ is —NH—; and

R⁷ is phenyl substituted with 2 methyl substituents.

Most preferred are those compounds selected from

4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide;

4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(1-phenylcyclohexyl)-1-piperazineacetamide;

1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-[4-[α-(1-pyrrolidinylcarbonyl)-benzyl]-1-piperazinyl]piperidine;

1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-[1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-yl]-1-piperazinyl]-2-phenylmethyl)piperidine;

4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(4-trifluoromethylphenyl)methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide;

4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(3,4-dichlorophenyl)methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide; the N-oxides, the stereoisomeric forms and pharmaceuticallyacceptable addition salts thereof.

Particularly interesting stereoisomeric forms are

(+)-(B)-trans-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide; and

(−)-(B)-cis-4-[1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide, and the pharmaceutically acceptable addition salts thereof,especially the (L)-malic acid form.

The compounds of formula (I) can be prepared by reductively N-alkylatingan intermediate of formula (III) with an intermediate of formula (II).Said reductive N-alkylation may be performed in a reaction-inert solventsuch as, for example, dichloromethane, ethanol, toluene or a mixturethereof, and in the presence of an appropriate reducing agent such as,for example, a borohydride, e.g. sodium borohydride, sodiumcyanoborohydride or triacetoxy borohydride. In case a borohydride isused as a reducing agent, it may be convenient to use a complex-formingagent such as, for example, titanium (IV) isopropylate as described inJ. Org. Chem, 1990, 55, 2552-2554. Using said complex-forming agent mayalso result in an improved cis/trans ratio in favour of the transisomer. It may also be convenient to use hydrogen as a reducing agent incombination with a suitable catalyst such as, for example,palladium-on-charcoal or platinum-on-charcoal. In case hydrogen is usedas reducing agent, it may be advantageous to add a dehydrating agent tothe reaction mixture such as, for example, aluminum tert-butoxide. Inorder to prevent the undesired further hydrogenation of certainfunctional groups in the reactants and the reaction products, it mayalso be advantageous to add an appropriate catalyst-poison to thereaction mixture, e.g., thiophene or quinoline-sulphur. Stirring andoptionally elevated temperatures and/or pressure may enhance the rate ofthe reaction.

In this and the following preparations, the reaction products may beisolated from the reaction medium and, if necessary, further purifiedaccording to methodologies generally known in the art such as, forexample, extraction, crystallization, trituration and chromatography.

The compounds of formula (I) can also be prepared by reacting anintermediate of formula (IV) wherein W¹ is an appropriate leaving groupsuch as, for example, a halogen, e.g. chloro or bromo, or a sulfonyloxyleaving group, e.g. methanesulfonyloxy or benzenesulfonyloxy, with anintermediate of formula (V). The reaction can be performed in areaction-inert solvent such as, for example, a chlorinated hydrocarbon,e.g. dichloromethane, an alcohol, e.g. ethanol, or a ketone, e.g. methylisobutylketone, and in the presence of a suitable base such as, forexample, sodium carbonate, sodium hydrogen carbonate or triethylamine.Stirring may enhance the rate of the reaction. The reaction mayconveniently be carried at a temperature ranging between roomtemperature and reflux temperature.

The compounds of formula (I) may also be converted into each otherfollowing art-known transformation. In particular, the compounds offormula (I) wherein L is other than hydrogen, said L being representedby L and said compounds being represented by formula (I-a), can also beprepared by reacting a compound of formula (I) wherein L is hydrogen,said compounds being represented by formula (I-b), with an intermediateof formula (VI) wherein W² is an appropriate leaving group such as, forexample, a halogen, e.g. chloro or bromo, or a sulfonyloxy leavinggroup, e.g. methanesulfonyloxy or benzenesulfonyloxy, at reactionconditions which are similar to those for the reaction betweenintermediates of formula (IV) and (V).

Compounds of formula (I-b) may be prepared by reductively N-alkylating apiperazine derivative of formula (VII) wherein P¹ is a protective groupsuch as, for example, benzyl, with an intermediate of formula (II). Saidreaction may be performed in a similar way as described hereinabove forthe reductive N-alkylation using intermediates (II) and (III). The thusformed compound of formula (I-c) may then be deprotected using art-knowndeprotection techniques. Depending on the nature of the protective groupP₁, compounds of formula (I-c) may be part of the scope of the compoundsof formula (I).

Alternatively, compounds of formula (I-b) may be prepared by firstreductively N-alkylating a piperazine derivative of formula (VII)wherein P¹ is a protective group such as, for example, halo, with anintermediate of formula (VIII) using the same procedure as describedhereinabove for the reductive N-alkylation using intermediates (II) and(III). The thus formed intermediate of formula (XI) may then be reactedwith an intermediate of formula (IV) in a reaction-inert solvent andoptionally in the presence of a suitable base such as, for example,triethylamine, to form a compound of formula (I-c), which may then bedeprotected using art-known deprotection techniques.

The compounds of formula (I-b) are deemed to be of particular use in thesynthesis of other compounds of formula (I).

The compounds of formula (I) may also be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I) with anappropriate organic or inorganic peroxide. Appropriate inorganicperoxides comprise, for example, hydrogen peroxide, alkali metal orearth alkaline metal peroxides, e.g. sodium peroxide, potassiumperoxide; appropriate organic peroxides may comprise peroxy acids suchas, for example, benzencarboperoxoic acid or halo substitutedbenzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid,peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g.tert-butyl hydroperoxide. Suitable solvents are, for example, water,lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvent.

The starting materials and some of the intermediates are known compoundsand are commercially available or may be prepared according toconventional reaction procedures generally known in the art. Forexample, intermediates of formula (III), (IV) and (VI) may be preparedaccording to art-known procedures.

Intermediates of formula (II) may be prepared by condensing anintermediate of formula (IV) with an intermediate of formula (VIII)analogous to the procedure described in EP-0,532,456-A.

The preparation of intermediates of formula (VIII) is also described inEP-0,532,456-A. However, intermediates of formula (VIII) wherein R¹ isoptionally substituted Ar¹C₁₋₆alkyl or di(Ar¹)C₁₋₆alkyl, said R¹ beingrepresented by —CH(R^(1a) )₂ and said intermediates being represented byformula (VIII-a), may also be prepared as depicted in scheme I.

In scheme 1, the intermediates of formula (IX-b) may be prepared byreacting an intermediate of formula (IX-a) with an aldehyde or a ketoneof formula (X). The C₁₋₆alkylcarbamate moiety in the intermediates offormula (IX-b) may be converted into a fused oxazolone which in turn maybe reduced to an intermediate of formula (IX-d). Said intermediate(IX-d) may in turn be deprotected, thus forming an intermediate (IX-d)may it turn be deprotected, thus forming an intermediate of formula(VIII-a). Subsequently, intermediates of formula (VIII-a) may be reactedwith an intermediate of formula (IV) to prepare intermediates of formula(II) wherein R¹ is defined as —CH(R^(1a))₂, said intermediates beingrepresented by formula (II-a).

Said intermediates of formula (II-a) may also be prepared by firstreacting intermediate (IX-d) with intermediate (IV) in the presence of asuitable base to form an intermediate of formula (XII), which maysubsequently be deprotected. These reactions and those performed inscheme 1 may all be conducted following conventional methods that aregenerally known in the art.

Intermediates of formula (V) may suitably be prepared by reacting anintermediate of formula (VIII-1), being a protected intermediate offormula (VIII) with a protecting group P² such as, for example, aC₁₋₆alkyloxycarbonyl group, with an intermediate of formula (III)according to the previously described reductive N-alkylation procedure,and subsequently deprotecting the thus formed intermediate.

In particular, intermediates of formula (V) wherein R¹ is —CH(R^(1a))₂,said intermediates being represented by formula (V-a), may be preparedas is depicted in scheme 2.

The ketalized intermediate of formula (IX-c) may be transformed to thecorresponding ketone of formula (IX-e) which subsequently may bereductively aminated with a piperazine- or homopiperazine derivative offormula (III). The thus obtained intermediate may then be reduced with asuitable reducing agent to an intermediate of formula (V-a).

Pure stereochemically isomeric forms of the compounds of formula (I) maybe obtained by the application of art-known procedures. Diastereomersmay be separated by physical methods such as selective crystallizationand chromatographic techniques, e.g., counter-current distribution,liquid chromatography and the like.

The compounds of formula (I) as prepared in the hereinabove describedprocesses are generally racemic mixtures of enantiomers which can beseparated from one another following art-known resolution procedures.The racemic compounds of formula (I) which are sufficiently basic oracidic may be converted into the corresponding diastereomeric salt formsby reaction with a suitable chiral acid, respectively chiral base. Saiddiastereomeric salt forms are subsequently separated, for example, byselective or fractional crystallization and the enantiomers areliberated therefrom by alkali or acid. An alternative manner ofseparating the enantiomeric forms of the compounds of formula (I)involves liquid chromatography, in particular liquid chromatographyusing a chiral stationary phase. Said pure stereochemically isomericforms may also be derived from the corresponding pure stereochemicallyisomeric forms of the appropriate starting materials, provided that thereaction occurs stereospecifically. Preferably if a specificstereoisomer is desired, said compound will be synthesized bystereospecific methods of preparation. These methods will advantageouslyemploy enantionmerically pure starting materials.

The compounds of formula (I) have valuable pharmacological properties inthat they interact with tachykinin receptors and they antagonizetachykinin-induced effects, especially substance P-induced effects, bothin vivo and in vitro and are thus of use in the treatment oftachykinin-mediated diseases, and in particular in substance P-mediateddiseases.

Tachykinins, also referred to as neurokinins, are a family of peptidesamong which substance P (SP), neurokinin A (NKA), neurokinin B (NKB) andneuropeptide K (NPK) may be identified. They are naturally occurring inmammals, including human beings, and are distributed throughout thecentral and peripheral nervous system, where they act asneurotransmitters or neuromodulators. Their actions are mediated throughseveral subtypes of receptors, such as, for example, NK₁, NK₂ and NK₃receptors. Substance P displays highest affinity for NK₁ receptors,whereas NKA preferentially binds to NK₂ receptors and NKB preferentiallybinds to NK₃ receptors. However, the selectivity of these tachykinins isrelatively poor and under physiological conditions the actions of any ofthese tachykinins might be mediated by activation of more than onereceptor type.

Substance P and other neurokinins are involved in a variety ofbiological actions such as pain transmission (nociception), neurogenicinflammation, smooth muscle contraction, plasma protein extravasation,vasodilation, secretion, mast cell degranulation, and also in activationof the immune system. A number of diseases are deemed to be engenderedby activation of neurokinin receptors, in particular the NK₁ receptor,by excessive release of substance P and other neurokinins in particularcells such as cells in the neuronal plexi of the gastrointestinal tract,unmyelinated primary sensory afferent neurons, sympathetic andparasympathetic neurons and nonneuronal cell types (DN&P 8(1), February1995, p. 5-23, “Neurokinin Receptors” by Longmore J. et al.;Pharmacological Reviews 46(4), 1994, p. 551-599, “Receptors andAntagonists for Substance P and Related Peptides” by Regoli et al.).

The compounds of the present invention are potent inhibitors ofneurokinin-mediated effects, in particular those mediated via the NK₁receptor, and may therefore be described as tachykinin antagonists,especially as substance P antagonists, as indicated in vitro by theantagonism of substance P induced relaxation of pig coronary arterieswhich is described hereinafter. The binding affinity of the presentcompounds for the human, guinea-pig and gerbil neurokinin receptors maybe determined in vitro in a receptor binding test using ³H-substance-Pas radioligand. The subject compounds also show substance-P antagonisticactivity in vivo as may be evidenced by, for instance, the antagonism ofsubstance P-induced plasma extravasation in guinea-pigs, or theantagonism of drug-induced emesis in ferrets (Watson et al., Br. J.Pharmacol. 115, 84-94, 1995).

In view of their capability to antagonize the actions of tachykinins byblocking the tachykinin receptors, and in particular antagonizing theactions of substance P by blocking the NK₁ receptor, the subjectcompounds are useful in the prophylactic and therapeutic treatment oftachykinin-mediated diseases such as, for example,

pain, in particular traumatic pain such as postoperative pain; traumaticavulsion pain such as brachial plexus; chronic pain such as arthriticpain such as occurring in osteo-rheumatoid or psoriatic arthritis;neuropathic pain such as post-herpetic neuralgia, trigeminal neuralgia,segmental or intercoastal neuralgia, fibromyalgia, causalgia, peripheralneuropathy, diabetic neuropathy, chemotherapy-induced neuropathy,AIDS-related neuropathy, occipital neuralgia, geniculate neuralgia,glossopharyngeal neuralgia, reflex sympathetic dystrophy, phantom limbpain; various forms of headache such as migraine, acute or chronictension headache, temperomandibular pain, maxillary sinus pain, clusterheadache; odontalgia; cancer pain; pain of visceral origin;gastrointestinal pain; nerve entrapement pain; sport's injury pain;dysmennorrhoea; menstrual pain; meningitis; arachnoiditis;musculoskeletal pain; low back pain e.g. spinal stenosis; prolapseddisc; sciatica; angina; ankylosing spondyolitis; gout; burns; scar pain;itch; and thalmaic pain such as post stroke thalamic pain;

respiratory and inflammatory diseases, in particular inflammation inasthma, influenza, chronic bronchitis and rheumatoid arthritis;inflammatory diseases of the gastrointestinal tract such as Chrohn'sdisease, ulcerative colitis, inflammatory bowel disease andnon-steroidal anti-inflammatory drug induced damage; inflammatorydiseases of the skin such as herpes and eczema; inflammatory diseases ofthe bladder such as cystitis and urge incontinence; and eye and dentalinflammation;

emesis, i.e. nausea, retching and vomiting, including acute emesis,delayed emesis and anticipatory emesis, no matter how emesis is induced,for example, emesis may be induced by drugs such as cancerchemotherapeutic agents such as alkylating agents, e.g.cyclophosphamide, carmustine, lomustine and chlorambucil; cytotoxicantibiotics, e.g. dactinomycin, doxorubicin, mitomycin-C and bleomycin;anti-metabolites, e.g. cytarabine, methotrexate and 5-fluorouracil;vinca alkaloids, e.g. etoposide, vinblastine and vincristine; and otherssuch as cisplatin, dicarbazine, procarbazine and hydroxyurea; andcombinations thereof; radiation sickness; radiation therapy, e.g.irradiation of the thorax or abdomen, such as in the treatment ofcancer; poisons; toxins such as toxins caused by metabolic disorders orby infection, e.g. gastritis, or released during bacterial or viralgastrointestinal infection; pregnancy; vestibular disorders, such asmotion sickness, vertigo, dizziness and Ménière's disease;post-operative sickness; gastrointestinal obstruction; reducedgastrointestinal motility; visceral pain, e.g. myocardial infarction orperitonitis; migrane; increased intercranial pressure; decreasedintercranial pressure (e.g. altitude sickness); opioid analgesics, suchas morphine; and gastrooesophageal reflux disease, acid indigestion,over-indulgence of food or drink, acid stomach, sour stomach,waterbrash/regurgitation, heartburn, such as episodic heartburn,nocturnal heartburn, and meal-induced heartburn and dyspepsia;

central nervous system disorders, in particular psychoses such asschizophrenia, mania, dementia or other cognitive disorders e.g.Alzheimer's disease; anxiety; AIDS-related dementia; diabeticneuropathy; multiple sclerosis; depression; Parkinson's disease; anddependence on drugs or substances of abuse;

allergic disorders, in particular allergic disorders of the skin such asurticaria, and allergic disorders of the airways such as rhinitis;

gastrointestinal disorders, such as irritable bowel syndrome;

skin disorders, such as psoriasis, pruritis and sunburn;

vasospactic diseases, such as angina, vascular headache and Reynaud'sdisease;

cerebral ischaemia, such as cerebral vasospasm following subarachnoidhaemmorhage;

stroke, epilepsie, head trauma, spinal cord trauma and ischemic neuronaldamage;

fibrosing and collagen diseases, such as scleroderma and eosinophilicfascioliasis;

disorders related to immune enhancement or suppression, such as systemiclupus erythematosus;

rheumatic diseases, such as fibrositis;

neoplastic disorders;

cell proliferation; and

cough.

The compounds of the present invention have a favourable metabolicstability and exhibit good oral availability. They also have anadvantageous onset and duration of action. The compounds of formula (I)also have the ability to penetrate the central nervous system as may bedemonstrated in vivo by their inhibitory effect on the change inbehaviour induced by intracerebroventricular-applied substance P in thegerbil.

In view of the utility of the compounds of formula (I), there isprovided a method of treating warm-blooded animals, including human,suffering from tachykininmediated diseases as mentioned hereinabove, inparticular, pain, emesis or asthma. Said method comprises the systemicadministration of an effective tachykinin antagonizing amount of acompound of formula (I), a N-oxide form, a pharmaceutically acceptableaddition salt or a possible stereoisomeric form thereof, to warm-bloodedanimals, including humans. Hence, the use of a compound of formula (I)as a medicine is provided, and in particular a medicine to treat pain,emesis or asthma.

For ease of administration, the subject compounds may be formulated intovarious pharmaceutical forms for administration purposes. To prepare thepharmaceutical compositions of this invention, a therapeuticallyeffective amount of the particular compound, optionally in addition saltform, as the active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which may take a wide variety offorms depending on the form of preparation desired for administration.These pharmaceutical compositions are desirably in unitary dosage formsuitable, preferably, for administration orally, rectally,percutaneously, or by parenteral injection. For example, in preparingthe compositions in oral dosage form, any of the usual pharmaceuticalmedia may be employed, such as, for example, water, glycols, oils,alcohols and the like in the case of oral liquid preparations such assuspensions, syrups, elixirs and solutions; or solid carriers such asstarches, sugars, kaolin, lubricants, binders, disintegrating agents andthe like in the case of powders, pills, capsules and tablets. Because oftheir ease in administration, tablets and capsules represent the mostadvantageous oral dosage unit form, in which case solid pharmaceuticalcarriers are obviously employed. For parenteral compositions, thecarrier will usually comprise sterile water, at least in large part,though other ingredients, for example, to aid solubility, may beincluded. Injectable solutions, for example, may be prepared in whichthe carrier comprises saline solution, glucose solution or a mixture ofsaline and glucose solution. Injectable solutions containing compoundsof formula (I) may be formulated in an oil for prolonged action.Appropriate oils for this purpose are, for example, peanut oil, sesameoil, cottonseed oil, corn oil, soy bean oil, synthetic glycerol estersof long chain fatty acids and mixtures of these and other oils.Injectable suspensions may also be prepared in which case appropriateliquid carriers, suspending agents and the like may be employed. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewettable agent, optionally combined with suitable additives of anynature in minor proportions, which additives do not cause anysignificant deleterious effects on the skin. Said additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as a spot-onor as an ointment. Acid or base addition salts of compounds of formula(I) due to their increased water solubility over the corresponding baseor acid form, are obviously more suitable in the preparation of aqueouscompositions.

In order to enhance the solubility and/or the stability of the compoundsof formula (I) in pharmaceutical compositions, it can be advantageous toemploy α-, β- or γ-cyclodextrins or their derivatives, in particularhydroxyalkyl substituted cyclodextrins, e.g.2-hydroxypropyl-β-cyclodextrin. Also co-solvents such as alcohols mayimprove the solubility and/or the stability of the compounds of formula(I) in pharmaceutical compositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

Those of skill in the treatment of tachykinin mediated diseases coulddetermine the effective therapeutic daily amount from the test resultspresented hereinafter. An effective therapeutic daily amount would befrom about 0.001 mg/kg to about 40 mg/kg body weight, more preferablyfrom about 0.01 mg/kg to about 5 mg/kg body weight. It may beappropriate to administer the therapeutically effective dose once dailyor as two, three, four or more sub-doses at appropriate intervalsthroughout the day. Said sub-doses may be formulated as unit dosageforms, for examples, containing 0.05 mg to 500 mg, and in particular,0.5 mg to 50 mg of active ingredient per unit dosage form.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weightand general physical condition of the particular patient as well asother medication the patient may be taking, as is well known to thoseskilled in the art. Furthermore, it is evident that said effective dailyamount may be lowered or increased depending on the response of thetreated patient and/or depending on the evaluation of the physicianprescribing the compounds of the instant invention. The effective dailyamount ranges mentioned hereinabove are therefore only guidelines.

The following examples are intended to illustrate and not to limit thescope of the present invention

Experimental Part

Hereinafter “RT” means room temperature, “THF” means tetrahydrofuran,“DIPE” means diisopropylether, “DCM” means dichloromethane and “DMF”means N,N-dimethylformamide.

A. Preparation of the Intermediate Compounds EXAMPLE A.1

a) A mixture of (±)-1,1-dimethyl7-(phenylmethyl)-1,4-dioxa-8-azaspiro[4,5]decane-8-carboxylate (13 g;prepared according to the method described in EP-A-532,456) in HCl (6N;130 ml) was stirred and refluxed for 3 hours. The reaction mixture wascooled, alkalized with aqueous NaOH (50%) and extracted with DCM. Theorganic layer was separated, dried, filtered, and the filtrate, whichcontained (±)-2-(phenylmethyl)-4-piperidinone (intermediate 1), was usedin next reaction step.

b) A mixture of the filtrate obtained in the previous reaction step,3,5-dimethylbenzoyl chloride (7.4 g) and triethylamine (11 ml) wasstirred overnight at RT. The reaction mixture was extracted with diluteNaOH solution. The organic layer was separated, dried, filtered and thesolvent evaporated. The residue was crystallized from DIPE. Theprecipitate was filtered off and dried, yielding 7.44 g (58%) of(±)-1-(3,5dimethylbenzoyl)-2-(phenylmethyl)-4-piperidinone (intermediate2; mp. 107.8° C.)

Example A.2

a) A mixture of (35)-1,1-dimethyl7-(phenylmethyl)-1,4-dioxa-8-azaspiro[4,5]decane-8-carboxylate (33.34 g;prepared according to the method described in EP-A-532,456) in HCl (6N;250 ml) was stirred at 70° C. for 1 hour and 30 minutes. The mixture wascooled, alkalized with NaOH while cooling to 25° C., and extracted withDCM (100 ml). The organic layer was separated and the aqueous layer wasextracted with CH₂Cl₂. Triethylamine (20.2 g), followed by3,5-bis(trifluoromethyl)benzoyl chloride. (27.7 g) dissolved in a littleDCM were added and the mixture was stirred for 2 hours. The mixture wasextracted with water, and the layers were separated. The organic layerwas dried, filtered and the solvent evaporated. The residue wascrystallized from DIPE, the precipitate was filtered off and dried,yielding 18.34 g product. The mother layer was evaporated and theresidue was crystallized from DIPE. The precipitate was filtered off anddried, yielding 6.51 g of product. The two fraction were put togetherand taken up in water and DCM, NaOH was added and the mixture wasextracted. The organic layer was dried, filtered and the solventevaporated, yielding 16.14 g (38%) of (35)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinone (intermediate 3; mp. 102.5°C.).

Example A.3

A mixture of pyrrolidine (2.13 g) and triethylamine (6.06 g) in DCM (100ml) was stirred at −10° C. 2-chloro-2-phenylacetylchloride (5.67 g) wasadded slowly and dropwise. The mixture was allowed to warm to RT and wasthen stirred overnight. The mixture was extracted with water and K₂CO₃.The separated organic layer was dried, filtered and the solvent wasevaporated. The residue was crystallized from DIPE and the precipitatewas filtered off and dried, yielding 3.25 g (48%) of fraction 1. Themother layer was separated and the solvent was evaporated. The residuewas crystallized from DIPE and the precipitate was filtered off anddried, yielding 0.29 g (5%) of fraction 2. Both fractions were combined,thus yielding 3.54 g (53%) of (±)-1-(2-chloro-2-phenylacetyl)pyrrolidine(intermediate 4; mp. 88.5° C.).

Example A.4

Sodium hydride (2 g) was added portionwise to a solution of3,5-dimethylphenol (6.1 g) in DMF (50 ml). The mixture was stirred for30 minutes and added dropwise at a temperature below 30° C. to asolution of 2-chloro-2-phenylacetylchloride (9.45 g) in DMF (50 ml). Themixture was stirred overnight, decomposed with water (5 ml) and thesolvent was evaporated. Water was added and the mixture was extractedwith DCM. The separated organic layer was dried, filtered and thesolvent was evaporated. The residue was purified over silica gel on aglass filter (eluent: hexane/DIPE 100/0, 98/2 and 95/5). The purefractions were collected and the solvent was evaporated [residue;yielding 10.82 g (79%)]. A small amount of the obtained residue wascrystallized from DIPE, the precipitate was filtered off and the solventwas evaporated, yielding 1 g of (±)-3,5-dimethylphenylα-chlorobenzeneacetate (intermediate 5; mp. 79.0° C.).

Example A.5

a) A mixture of(±)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-(1-piperazinyl)piperidine(0.0127 mol), chloroacetonitrile (0.013 mol) and sodium carbonate (0.013mol) in methylisobutyl keton (100 ml) was stirred and refluxed. Themixture was cooled and water was added. The organic layer was separated,dried, filtered and the solvent was evaporated. The residue was purifiedover silica gel on a glass filter (eluent: CH₂Cl₂/CH₃OH 100/0, 99.5/0.5and 99/1). The pure fractions were collected and the solvent wasevaporated, yielding 3.64 g (53%) of (±)-cis-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(cyanomethyl)-1-piperazinyl]-2-(phenylmethyl)piperidine(intermediate 6).

b) A mixture of intermediate 6 (0.0067 mol) in THF (150 ml) washydrogenated at 20° C. with Raney Nickel (1 g) as a catalyst. Afteruptake of hydrogen, the catalyst was filtered off and the filtrate wasevaporated, yielding 3.77 g of(±)-cis-4-[4-(2-aminoethyl)-1-piperazinyl]-1-[3,5-(trifluoromethyl)benzoyl]-2-(phenylmethyl)piperidine(intermediate 7).

Example A.6

A mixture of 1-(phenylmethyl)-4-piperidinone (0.2 mol) and1-methylpiperazine (0.2 mol) in methanol (500 ml) was hydrogenated for 8hours with palladium on activated carbon (10%, 2.5 g) as a catalyst.After uptake of hydrogen, the catalyst was filtered off and the filtratewas evaporated. A mixture of di-tert-butyl dicarbonate (0.2 mol) in THF(500 ml) was added to the residue and hydrogenated again with palladiumon activated carbon (10%, 2.5 g) as a catalyst. After uptake ofhydrogen, the catalyst was filtered off and the filtrate was evaporated.The residue was purified over silica gel on a glass filter (eluent:CH₂Cl₂/CH₃OH 95/5). The pure fractions were collected and the solventwas evaporated, yielding 45.3 g (80%) of 1,1-dimethylethyl4-(4-methyl-1-piperazinyl)-1-piperidinecarboxylate (intermediate 8).

Example A.7

a) A mixture of 4-methoxypyridine (0.4 mol) in THF (1000 ml) was stirredand cooled in a 2-propanol/CO₂ bath. Ethyl chloroformate (0.4 mol) wasadded dropwise and the mixture was stirred for 3 hours while cooling(mixture I). In another round-bottom flask, the Grignard-reagent wasprepared: MG (0.44 mol) was stirred in a small amount of (C₂H₅)₂O. SomeI₂ was added. A small amount of 1,2-dichloro-4-(chloromethyl)benzene wasadded. Then, 1,2-dichloro-4-(chloromethyl)benzene (0.4 mol) in (C₂H₅)₂O(600 ml) was added dropwise at reflux temperature. The mixture wasstirred for one hour (mixture II). The Grignard-reagent was decantedoff, added to mixture I at <−40° C., and the resulting reaction mixturewas stirred, allowing the temperature to reach RT. The reaction mixturewas stirred for one hour at RT. HCl (10%, 800 ml) was added and themixture was stirred for 30 minutes, then CH₂Cl₂ was added. The organiclayer was separated, dried, filtered and the solvent evaporated,yielding 57.8 g (44%) of (±)-ethyl6-[(3,4-dichlorophenyl)methyl]-1,2,3,4-tetrahydro-4-oxo-1-pyridinecarboxylate(intermediate 9).

b) Intermediate 9 (0.176 mol) in THF (880 ml) was stirred under a N₂flow, and cooled to −78° C. L-selectride (0.264 mol) was added dropwiseat −78° C. The reaction mixture was stirred for 1 hour, then poured outinto water, DIPE was added. The organic layer was separated, washed withan aqueous NaHCO₃ solution, with an aqueous NaCl solution, dried,filtered and the solvent was evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 90/10). Thedesired fractions were collected and the solvent was evaporated,yielding 20.2 g (34.8%) of (±)-ethyl2-[(3,4-dichlorophenyl)methyl]-4-oxo-1-piperidinecarboxylate(intermediate 10).

c) Titanium (IV)isopropoxide (0.0269 mol) was added to a mixture ofintermediate 10 (0.0224 mol) and intermediate 10 (0.0224 mol) in DCM (11ml). The mixture was stirred at RT for 3 hours. Sodium cyanoborohydride(0.0224 mol) and the ethanol (10 mixture was stirred. CH₂Cl₂ was addedan the mixture was stirred. The organic layer was separated, dried,filtered and the solvent was evaporated. The residue was purified byHPLC over silica gel (eluent: CH₂Cl₂/CH₃OH 100/0 and 98/2). The purefractions were collected and the solvent was evaporated. The residue waspurified by reversed phase chromatography (eluent: NH₄OAc(0.5% inH₂O)/CH₃OH 20/80). Two pure fractions were collected and their solventswere evaporated. The residue was dried and ground, yielding 2 g (16%) of(±)-ethyltrans-2-[(3,4-dichlorophenyl)methyl]-4-[4-[2-[2,6-dimethylphenyl)amino]-2-oxoethyl]-1-piperazinyl]-1-piperidinecarboxylate (intermediate11) and 3.5 g (28%) of (±)-ethyl cis-2-[(3,4-dichlorophenyl)methyl]-4-[4-[2-[(2,6-dimethylphenyl)amino]-2-oxoethyl]-1-piperazinyl]-1-piperidinecarboxylate (intermediate12).

d) A mixture of intermediate 11 (0.0034 mol) and potassium hydroxide(0.034 mol) in 2-propanol (150 ml) was stirred and refluxed for 4 days.The solvent was evaporated. The residue was taken up in CH₂/Cl₂/water.The organic layer was separated, dried, filtered and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH/NH₃) 95/5). The pure fractions werecollected and the solvent was evaporated, yielding 0.5 g (30%) of(±)-trans-4-[2-[(3,4-dichlorophenyl)methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)1-piperazineacetamide(intermediate 13).

Example A.8

a) Sec-butyllithium (0.066 mol) was added to a mixture of1,1-dimethylethyl 1,4-dioxo-8-azaspiro[4.5]-8-carboxylate (0.06 mol) inN,N,N′,N′-tetramethylethylenediamine (22.6 ml) and (C₂H₅)₂O (100 ml).The mixture was stirred at −70° C. for 3 hours. 3,5-difluorobenzaldehyde(0.07 mol) was added dropwise at −70° C. The mixture was allowed to warmto RT. Water (50 ml) and DIPE were added. The aqueous layer wasseparated and extracted with CH₂Cl₂. The combined organic layer wasdried, filtered and the solvent was evaporated. Toluene was added andevaporated again, yielding 23 g of (35)-1,1-dimethyl7-[(3,5-difluorophenyl)hydroxymethyl]-1,4-dioxo-8-azaspiro[4,5]-8-carboxylate (intermediate14).

b) A mixture of intermediate 14 (0.06 mol) and 2-methyl-2-propanol,potassium salt (0.72 g) in toluene (110 ml) was stirred and refluxed for2 hours. The solvent was evaporated. The residue was stirred inpetroleum ether and a small amount of water, and decanted. The residuewas dissolved in CH₂Cl₂, dried, filtered and the solvent was evaporated.The residue was purified by column chromatography over silica gel(eluent: CH₂Cl₂/CH₃OH 100/0, 99/1 and 98/2). Two pure fractions werecollected and their solvents were evaporated, yielding 9.2 g (49%) of(±)-3-(3,5-difluorophenyl)tetrahydrospirol[1,3-dioxolan-2,5′(3′H-1H-oxazolo[3,4-a]pyridin]-1-one(intermediate 15).

c) A mixture of intermediate 15′(0.03 mol) in methanol (250ml) washydrogenated at 50° C. with palladium on activated carbon (10%, 2 g) asa catalyst. After uptake of hydrogen, the catalyst was filtered off andthe filtrate was evaporated. The residue was purified over silica gel ona glass filter (eluent: CH₂Cl₂/CH₃OH 100/0, 98/2 and 95/5 andCH₂Cl₂/(CH₃OH/NH₃) 95/5). The desired fractions were collected and thesolvent was evaporated, yielding 1.9 g (39%) of(35)-7-[(3,5-difluorophenyl)methyl]-1,4-dioxo-8-azaspiro[4,5]decane(intermediate 16).

d) A mixture of intermediate 16 (0.012 mol) in HCl 6N (30 ml) wasstirred at 75° C. for 2 hours. The mixture was cooled, poured out intoice and a NaOH solution and extracted with CH₂Cl₂. The organic layer wasseparated, dried and filtered, yielding 2.7 g of(±)-2-[(3,4-difluorophenyl)methyl]-4-piperidinone (intermediate 17).

e) A mixture of 3,5-tirfluoromethylbenzoyl chloride (0.012 mol) in asmall amount of CH₂Cl₂ was added dropwise to a stirred mixture ofintermediate 17 (0.012 mol) and N,N-diethylethanamine (0.024 mol). Themixture was stirred at RT for 1 hour and water was added. The organiclayer was separated, dried, filtered and the solvent was evaporated. Theresidue was purified over silica gel on a glass filter (eluent:CH₂Cl₂/CH₃OH 100/0 and 99.5/0.5). The pure fractions were collected andthe solvent was evaporated, yielding 2.7 g (48%) of (±)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(3,5-difluorophenyl)methyl]-4-piperidinone(intermediate 18).

Example A.9

Sec-butyllithium (0.63 mol) was added at −78° C. under N₂ flow to asolution of 1,1-dimethylethyl 1,4-dioxo-8-azaspiro[4,5]-8-carboxylate(0.57 mol) and N,N,N′,N′-tetramethylethylenediamine (1.14 mol) in(C₂H₅)₂O (1000 ml). One hour after complete addition, a mixture of3-(trifluoromethyl)benzaldehyde (0.57 mol) in (C₂H₅)₂O (200 ml) wasadded. The mixture was allowed to warm to RT and then stirred at RT for16 hours. The solvent was evaporated. A mixture of 2-methyl-2-propanol,potassium salt (0.2 mol) in toluene (500 ml) was added. The mixture wasstirred at 80° C. for 5 hours. The solvent was evaporated. The residuewas heated with a saturated NH₄Cl solution and extracted with CH₂Cl₂.The organic layer was separated, dried, filtered and the solvent wasevaporated. The residue was suspended in DIPE, filtered off and dried.This fraction was dissolved in CH₃OH (250 ml) and the mixture washydrogenated with palladium on activated carbon (10%, 3 g) as acatalyst. After uptake of hydrogen, the catalyst was filtered off andthe filtrate was evaporated. The residue was purified over silica gel ona glass filter (eluent: CH₂Cl₂/CH₃OH 95/5). The pure fractions werecollected and the solvent was evaporated. This fraction was dissolved inHCl (6N, 100 ml) and CH₃OH (100 ml) and the mixture was stirred at 50°C. for 8 hours. The organic solvent was evaporated. The concentrate waswashed with a saturated K₂CO₃ solution and extracted with CH₂Cl₂. Theorganic layer was separated, dried, filtered and the solvent wasevaporated. The residue was purified over silica gel on a glass filter(eluent: CH₂Cl₂/CH₃OH 95/5). The pure fractions were collected and thesolvent was evaporated, yielding 48.5 g (70%) of(±)-2-[[4-(trifluoromethyl)phenyl]methyl]-4-piperidinone (intermediate19).

Example A.10

a) A mixture of ethyl β-oxobenzenbutanoate (0.5 mol) andbenzenemethanamine (0.5 mol) in toluene (500 ml) was hydrogenated at120° C. (pressure=100 kg) overnight in the presence of Cu₂Cr₂O₅ (5 g)and CaO (10 g). After uptake of hydrogen, the catalyst was filtered offand the filtrate was evaporated, yielding 29.7 g (±)-ethyl N,2-bis(phenylmethyl)-β-alanine (intermediate 20).

b) Ethyl chloroacetate (0.3 mol) was added to a mixture of intermediate20 (0.2 mol) in DMF (250 ml). The mixture was stirred and triethylamine(0.4 mol) was added. The mixture was stirred at 60° C. overnight. Thesolvent was evaporated and the residue was taken up in water/CH₂Cl₂. Theorganic layer was separated, dried, filtered and the solvent wasevaporated, yielding 76.6 g of (±)-ethyl3-[(2-ethoxy-2-oxoethyl)(phenylmethyl)amino]benzenebutanoate(intermediate 21).

c) Intermediate 21 (0.2 mol) was heated to 80° C. under N₂ flow. NaOCH₃(44 g) was added. The mixture was stirred at 80° C. for 30 minutes. Thesolvent was evaporated and water (170 ml) and HCl (6N, 60 ml) wereadded. The mixture was stirred and refluxed for 1 hour, then cooled,alkalized and NaOH and extracted with CH₂Cl₂. The organic layer wasseparated, washed with water and a saturated NaCl solution, dried,filtered and the solvent was evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂/CH₃CN 100/0 and96/4). The pure fractions were collected and the solvent was evaporated,yielding 7.8 g of (±)-1,5-bis(phenylmethyl)-3-pyrrolidinone(intermediate 22).

d) A mixture of intermediate 22 (0.027 mol) and CH₃SO₃H (0.03 mol) inTHF (200 ml) was hydrogenated with palladium on activated carbon (10%, 2g) as a catalyst. After uptake of hydrogen, the catalyst was filteredoff, yielding (±)-5-(phenylmethyl)-3-pyrrolidinone methanesulfonate(1:1) (intermediate 23).

e) 3,5-di(trifluoromethyl)benzoyl chloride (0.03 mol) was added tointermediate 23 (0.027 mol). The mixture was stirred and triethylamine(0.1 mol) was added. The mixture was stirred at RT for 18 hours and thenwashed with water, NaOH and a saturated NaCl solution. The organic layerwas separated, washed with a saturated NaCl solution, dried, filteredand the solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 98/2). The purefractions were collected and the solvent was evaporated, yielding 1.4 gof(±)-1-[3,5-bis(trifluoromethyl)benzoyl]-5-(phenylmethyl)-3-pyrrolidinone(intermediate 24).

B. Preparation of the Compounds of Formula (I) Example B.1

a) Titanium(IV)isopropoxide (16.5 g) was added to a mixture ofintermediate 3 (21.5 g) and 1-(phenylmethyl) piperazine (8.81 g) in DCM(35 ml). The mixture was stirred for 3 hours at RT. Sodiumcyanoborohydride (2.85 g) and ethanol (70 ml) were added and theresulting reaction mixture was stirred overnight at RT. Water (5 ml) andDCM were added. The biphasic mixture was filtered over dicalite, and thefilter residue was washed with DCM. The organic layer was separated,dried, filtered and the solvent was evaporated. The residue wascrystallized from CH₃CN and the precipitate was filtered off and dried,yielding 7.93 g (26.9%) of(±)-cis-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-[4-(phenylmethyl)-1-piperazinyl]piperidine(compound 16, mp. 143.8° C.).

b) The mother liquor was concentrated and the residue was purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 100/0, then99/1, 98/2, 97/3). The desired fractions ((A) and (B)) were collectedand their solvent was evaporated. The A-isomer was crystallized fromCH₃CN, filtered off and dried, yielding 1.11 g (4%) of compound 16. Thepure fractions of the B-isomer were concentrated, yielding 5.9 g (20%)of (±)-trans-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-[4-(phenylmethyl)-1-piperazinyl]piperidine.The impure fractions of the B-isomer were collected and the solvent wasevaporated. The residue was converted into the fumaric acid salt (1:2)in ethanol. The precipitate was filtered off and dried, yielding 1.89 g(±)-trans-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-[4-(phenylmethyl)-1-piperazinyl]piperidine(E)-2-butenedioate(1:2) (compound 17; mp. 240.3° C.).

Example B.2

A mixture of compound 16 (8.4 g) in methanol (250 ml) was hydrogenatedat 50° C. with palladium on activated carbon (10%) (2 g) as a catalyst.After uptake of H₂, the catalyst was filtered off and the filtrate wasevaporated; yielding 7 g (100%) of (±)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-(1-piperazinyl)piperidine (compound 15).

Example B.3

a) Titanium(IV)isopropoxide (13.2 g) was added to a mixture ofintermediate 3 (17.16 g) andN-(2,6-dimethylphenyl)-1-piperazineacetamide (9.88 g) in DCM (20 ml).This mixture was stirred for 3 hours at RT. Sodium cyanoborohydride(2.52 g) in ethanol (20 ml) was added and the resulting reaction mixturewas stirred overnight at RT. Water (10 ml) was added and the reactionmixture was extracted with DCM (800 ml). The organic layer wasseparated, dried, filtered and the solvent was evaporated. The residuewas taken up into water and this mixture was extracted with DCM. Theseparated organic layer was dried, filtered, and the solvent evaporated.The residue was prepurified by column chromatography over silica gel(eluent: CH₂Cl₂/CH₃OH 97/3). The desired fractions were collected andthe solvent was evaporated, giving 4 g of the trans-racemate. Resolutionwas obtained by purification over stationary phase Chiralcel OD (eluent:CH₃OH 100%). Two desired trans-fraction groups were collected and theirsolvent was evaporated, yielding 1.75 g fraction 1 and 2 g fraction 2.Fraction 1 was dissolved in DCM, filtered and the filtrate wasevaporated. The residue was dried, yielding 1.55 g (6%)(−)-(A)-trans-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide (compound 26; mp. 97.4° C.; [α]_(D) ²⁰=−5.81° (c=1% in DMF)).Fraction 2 was dissolved in DCM, filtered and the filtrate wasevaporated. The residue was dried, yielding 1.70 g (6%)(+)-(B)-trans-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazine acetamide (compound 27; mp. 96.8° C.; [α]_(D) ²⁰ =+5.71°(c=1% in DMF)).

b) Compound 27 was dissolved in warm 2-propanol and converted into the(L)-malic acid salt with a solution of (L)-malic acid in 2-propanol. Themixture was stirred for 2 hours and the precipitate was filtered off anddried, yielding(+)-(B)-trans-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide. (L)-malic acid (1:1) (compound 95).

Example B.4

A mixture of compound 15 (2.5 g), intermediate 5 (1.65 g) and sodiumcarbonate (0.64 g) in methylisobutylketon (50 ml) was stirred andrefluxed for 3 hours. The reaction mixture was washed and the separatedorganic layer was dried, filtered and the solvent was evaporated. Theresidue was purified over silica gel on a glass filter (eluent:CH₂Cl₂/CH₃OH 100/0 and 99.5/0.5). The pure fractions were collected andthe solvent was evaporated, yielding 1.59 g (43%) of(±)-3,5-dimethylphenyl cis-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-α-phenyl-1-piperazineacetatecompound 43; mp. 88.1° C.).

Example B.5

A mixture of intermediate 2 (3.2 g), 1-(diphenylmethyl) piperazine (2.5g) and aluminum tributoxide (2 g) in toluene (250 ml) was hydrogenatedfor 48 hours at 50° C., with palladium on activated carbon (10%; 2 g) asa catalyst in the presence of thiophene (4% solution; 1 ml). Afteruptake of hydrogen (1 equiv), the catalyst was filtered off and thefiltrate was evaporated. The residue was purified by high-performanceliquid chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 100/0,upgrading to 90/10). Two pure fractions were collected and their solventwas evaporated, resulting in residue 1 and residue 2. Residue 1 wassuspended in DIPE. The precipitate was filtered off and dried, yielding0.94 g (17%) of(±)-cis-1-(dimethylbenzoyl)-4-[4-(diphenylmethyl)-1-piperazinyl]-2-(phenylmethyl)piperidine (compound 12; mp. 100.8° C.). Residue 2 was dried, yielding0.2 g (3.6%) of(±)-trans-1-(dimethylbenzoyl)-4-[4-(diphenylmethyl)-1-piperazinyl]-2-(phenylmethyl)piperidine(compound 13).

Example B.6

A mixture of compound 15 (0.005 mol) and 1,2-epoxyethylbenzene (0.006mol) in methanol (50 ml) was stirred at RT for 1 hour. The mixture wasstirred and refluxed for 3 hours. The solvent was evaporated and theresidue was purified over silica gel on a glass filter (eluent:CH₂Cl₂/CH₃OH 100/0, 99/1 and 98/2). The pure fractions were collectedand the solvent was evaporated. The residue was purified by HPLC oversilica gel (eluent: CH₂Cl₂/CH₃OH 98/2 to 95/5). Two pure fractions werecollected and their solvents were evaporated. Each residue was dried,yielding 0.7 g (23%) of(±)-cis-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(2-hydroxy-2-phenylethyl)-1piperazinyl]-2-(phenylmethyl)piperidine(compound 60) and 0.23 g (7%) of(±)-cis-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(2-hydroxy-2-phenylethyl)-1piperazinyl]-2-(phenylmethyl)piperidine (compound 61).

Example B.7

Compound 15 (0.005 mol),2-chloro-1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazole (0.005 mol)and Cupper (0.005 mol) were stirred at 140° C. for 2 hours. The mixturewas cooled, dissolved in CH₂Cl₂, filtered and washed with CH₂Cl₂ and adiluted NH₄OH solution. The organic layer was separated, washed with adiluted NH₄OH solution, dried, filtered and the solvent was evaporated.The residue was purified over silica gel on a glass filter (eluent:CH₂Cl₂/CH₃OH 100/0, 99.5/0.5, 99/1, 98.5/1.5 and 98/2). The purefractions were collected and the solvent was evaporated. The residue wasdried, yielding 1.42 g (40%)(±)-cis-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-[1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-yl]-1-piperazinyl]-2-(phenylmethyl)piperidine(compound 70).

Example B.8

A mixture of intermediate 7 (0.0033 mol) and 3,5-dimethylbenzoylchloride (0.0035 mol) in DCM (50 ml) was stirred at RT for 15 minutes.Triethylamine (0.007 mol) was added and the mixture was stirred for RTfor 1 hour. Water was added. The organic layer was separated, dried,filtered and the solvent was evaporated. The residue was converted intothe fumaric acid salt (1:1) with 2-propanol. The precipitate wasfiltered off and dried. The residue was converted into the free basewith NaOH. The precipitate was filtered off and dried. The residue waspurified over silica gel on a glass filter (eluent: CH₂Cl₂/CH₃OH 100/0,99.5/0.5, 992/1, 98/2 and 97/3). The pure fractions were collected andthe solvent was evaporated. The residue was dried, yielding 0.8 g (36%)(±)-cis-N-[2-[4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-1-piperazinyl]ethyl]-3,5-dimethylbenzamide(compound 116).

Example B.9

A mixture of compound 74, prepared according to example B.4, (0.004 mol)in methanol (150 ml) was hydrogenated at 50° C. with palladium onactivated carbon (10%; 1 g) as a catalyst in the presence of thiophene(4% solution, 1 ml). After uptake of hydrogen, the catalyst was filteredoff and the filtrate was evaporated. The residue was crystallized fromDIPE. The precipitate was filtered off, washed with DIPE and dried. Thisfraction was dissolved in toluene. The mixture was filtered and thesolvent was evaporated. The residue was suspended in DIPE. Theprecipitate was filtered off and dried. This fraction was converted intothe fumaric acid salt (1:2O with a warm solution of fumaric acid (0.52g) in ethanol. The mixture was stirred for 6 hours. The precipitate wasfiltered off and dried, yielding 0.91 g (25%) of(±)-cis-N-(4-amino-2,6-dimethylphenyl)-4-[1-[3,5-(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-1-piperazineacetamide(E)-2-butenedioate(1:2) compound 129).

Example B.10

Sec-butyllithium (0.055 mol) was added at −78° C. under N₂ flow to asolution of 1,1-dimethylethyl4-(4-methyl-1-piperazinyl)-1-piperidinecarboxylate (0.05 mol) andN,N,N′,N′-tetramethylethylenediamine (0.1 mol) in (C₂H₅)₂) (50 ml). 2hours after complete addition, a mixture of benzaldehyde (0.05 mol) in(C₂H₅)₂O (50 ml) was added. The mixture was allowed to warm to RT andthen stirred at 25° C. for 16 hours. The solvent was evaporated and theresidue was washed with a saturated NH₄Cl solution and extracted withCH₂Cl₂. The organic layer was separated, dried, filtered and the solventwas evaporated. A solution of 2-methyl-2-propanol, potassium salt (0.02mol) in toluene (100 ml) was added to this fraction and the mixture wasstirred at 100° C. for 2 hours. The solvent was evaporated. The residuewas washed with a saturated NH₄Cl solution, extracted with CH₂Cl₂ anddecanted. The organic layer was dried, filtered and the solvent wasevaporated. The residue was purified over silica gel on a glass filter(eluent: CH₂Cl₂/CH₃OH 95/5). The pure fractions were collected and thesolvent was evaporated. This fraction was dissolved in methanol (150 ml)and hydrogenated with palladium on activated carbon (10%, 3 g) as acatalyst. After uptake of hydrogen, the catalyst was filtered off andthe filtrate was evaporated. The residue was purified over silica gel ona glass filter (eluent: CH₂Cl₂/CH₃OH 95/5). The pure fractions werecollected and the solvent was evaporated. This fraction was dissolved inDCM (20 ml) and Triethylamine (2 ml). 3,5-di(trifluoromethyl)benzoylchloride (0.0087 mol) was added to 0° C. 1 hour after complete addition,water was added and the mixture was extracted with CH₂Cl₂.The organiclayer was separated, dried, filtered and the solvent was evaporated. Theresidue was purified over silica gel on a glass filter (eluent:CH₂Cl₂/CH₃OH 95/5). The pure fractions were collected and the solventwas evaporated. This fraction was converted into the (E)-2-butenediocacid salt (1:2) with ethanol. The precipitate was filtered off anddried, yielding 4.7 g (74%) of (±)-cis-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(4-methyl-1-piperazinyl)-2-phenylmethyl) piperidine(E)-2-butenedioate (1:2) (compound 130).

Example B.11

A mixture of compound 15 (0.005 mol),N-[2-(3,4-dichlorophenyl)-4-[(methylsulfonyl)oxy]butyl]-N-methylbenzamide (0.0055 mol) and NaHCO₃ (0.0055 mol) in ethanol (50 ml) wasstirred and refluxed for 6 hours. The solvent was evaporated, theresidue was taken up in water and extracted with CH₂Cl₂. The organiclayer was separated, dried, filtered and the solvent was evaporated. Theresidue was purified over silica gel on a glass filter (eluent:CH₂Cl₂/CH₃OH 100/0, 99/1, 98/2 and 97/3). The pure fractions werecollected and the solvent was evaporated. The residue was converted intothe fumaric acid salt (1:2) with ethanol. The precipitate was filteredoff and dried, yielding 1.42 g (27%) of(±)-cis-N-[4-[4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-1-piperazinyl]-2-(3,4-dichlorophenyl)butyl]-N-Methylbenzamide (E)-2-butenedioate (1:2) (compound 93).

Example B.12

A mixture of(±)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(3,5-difluorophenyl)methyl]-4-piperidinone (0.0058 mol),N-(2,6-dimethylphenyl)-1-piperazineacetamide (0.0058 mol) andtitanium(IV)isopropoxide (0.0064 mol) in 2-propanol (5 ml) was stirredat RT overnight. NaBH₄ (0.0116 mol) and ethanol (15 ml) were added. Themixture was stirred for 2 day. Water (5 ml) was added and the mixturewas stirred for 10 minutes. CH₂C₂ (200 ml) was added. The organic layerwas separated, dried, filtered and the solvent was evaporated. Thisfraction was purified by HPLC over silica gel (eluent: CH₂Cl₂/CH₃OH 98/2to 90/10 over a 30-minute period). Two pure fractions (F1 and F2) werecollected and their solvents were evaporated. F1 was purified by columnchromatography over RP18 (eluent: NH₄OAc (0.5% in H₂O)/CH₃CN 40/60). Thepure fractions were collected and the solvent was evaporated. Theresidue was dried, yielding 0.33 g (8%) of (±)-cis-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(3,5-difluorophenyl)methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide(compound 132). F2 was purified by column chromatography over silica gel(eluent: CH₂Cl₂/CH₃OH 100/0 to 98/2 over a 30-minute period). The purefractions were collected and the solvent was evaporated. The residue wasdissolved in CH₂Cl₂, filtered and the solvent was evaporated. Theresidue was dried, yielding 0.24 g (6%) of(±)-trans-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(3,5-difluorophenyl)methyl]-4-piperdinyl]-N-( 2,6-dimethylphenyl)-1-piperazineacetamide(compound 133).

Example B.13

3,5 di(trifluoromethyl)benzoyl chloride (0.0011 mol) was added to amixture of (±)-trans-4-[2-[3,4-dichlorophenyl)methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide0.001 mol) in DCM (20 ml). The mixture was stirred for 5 minutes.Triethylamine (2 ml) was added. The mixture was stirred at RT for 3hours, washed with a diluted NaOH solution and with water, and thendried. The solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 96/4). The purefractions were collected and the solvent was evaporated. The residue wascrystallized from CH₃CN. The precipitate was filtered off and dried,yielding 0.32 g (44%) of (±)-trans-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(3,4-dichlorophenyl)methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide(compound 139).

Example B.14

A mixture of compound 15 (0.01 mol) andimidazo[1,2-pyridin-2-carboxaldehyde (0.01 mol) in methanol (250 ml) washydrogenated at RT overnight with palladium on activated carbon (10%, 2g) as a catalyst in the presence of thiophene (4% solution, 2 ml). Afteruptake of hydrogen, the catalyst was filtered off and the filtrate wasevaporated. The residue was purified over silica gel on a glass filter(eluent: CH₂Cl₂/CH₃OH 100/0, 99/1, 98/2, 97/3 and 96/4). The purefractions were collected and the solvent was evaporated. The residue wasconverted into the fumaric acid salt (1:2) from ethanol. The precipitatewas filtered off and dried, yielding 2.8 g (32%) of(±)-cis-[1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(imidazol[1,2-a]pyridin-2-ylmethyl)-1-piperazinyl]-2-phenylmethyl)piperidine (E)-2-butenedioate (1:2) compound 111).

Example B.15

(+)-(B-trans)-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide(0.003 mol) was dissolved in ethanol (20 ml). A solution of fumaric acid(0.003 mol) in ethanol (15 ml) was added and the mixture was stood for 7days. The precipitate was filtered off and dried, yielding 1.2 g of(B-trans)-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide(E)-2-butenedioate (1:1) (compound 128).

Example B.16

A mixture of(±)-1-[3,5-bis(trifluoromethyl)benzoyl]-5-(phenylmethyl)-3-pyrrolidinone(0.0037 mol) and N-(2,6-dimethylphenyl)-1-piperazineacetamide (0.0037mol) in methanol (150 ml) was hydrogenated at 50° C. with palladium onactivated carbon (10%, 1 g) as a catalyst in the presence of tiophenesolution (1 ml). After uptake of hydrogen, the catalyst was filtered offand the filtrate was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 95/5). The desiredfractions were collected and the solvent was evaporated. The residue wasdried and then crystallized from DIPE. The precipitate was filtered offand dried, yielding 0.35 g (15%) of(±)-cis-4-[1-[3,5bis(trifluoromethyl)benzoly]-5-(phenylmethyl)-3-pyrrolidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide(compound 1310.

Example B.17

(±)-cis-1-(phenylmethyl)-4-[2-(phenylmethyl)-1-piperidinyl]piperazine(0.00043 mol) was added to 3,4-dichlorobenzeneacetic acid (±0.0004 mol)and 1-hydroxybenzotriazole hydrate (0.080 g) in DCM (5 ml). The mixturewas stirred and cooled on an ice/ethanol-bath, under N₂ flow.Triethylamine was added dropwise. A solution of1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (0.120 g)in DCM (5 ml) was added and the reaction mixture was allowed to warm toRT, under N₂. The reaction mixture was stirred overnight. The mixturewas diluted with CH₂Cl₂, until a 15-mol total volume was obtained. Then,the compound was isolated and purified by HPLC over solica gel (eluent:CH₂Cl₂ to CH₂Cl₂/CH₃OH 90/10 over 20 minutes at 125 ml/minute). Thedesired fractions were collected and the solvent was evaporated,yielding 0.020 g of(±)-cis-1-[(3,4-dichlorophenyl)acetyl]-2-(phenylmethyl)-4-[4-(phenylmethyl)-1-piperazinyl]piperidine (compound 181).

Example B.18

3,5-di(trifluoromethyl)-1-isocyanatobenzene (0.0025 mol) in DCM (10 ml)was added to a mixture of(±)-trans-N-(2,-dimethylphenyl)-4-[2-(phenylmethyl)-4-piperidinyl]-1-piperazineacetamide(0.0025 mol) in DCM (15 ml). The mixture was stirred at RT overnight.The precipitate was filtered off and dried, yielding 0.66 g (40%) of(±)-trans-4-[1-[[[3,5-bis(trifluoromethyl)phenyl]amino]carbonyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide(compound 143).

Example B.19

A mixture of(±)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-4-piperidinone (0.01 mol) andN-(2,6-dimethylphenyl)-1-piperazine-acetamide (0.01 mol) in 2-propanol(150 ml) was hydrogenated at 50° C. with platinum on activated carbon(55), 2 g) as a catalyst in the presence of titanium(IV)isopropoxide(2.84 g) and thiophene solution (1 ml). After uptake of hydrogen, thecatalyst was filtered off and the filtrate was evaporated. The residuewas taken up in CH₂Cl₂ and H₂O. The organic layer was separated, washedseveral times with H₂O, dried, filtered over dicalite and the solventwas evaporated. This fraction was purified by HPLC over silica gel(eluent: CH₂Cl₂/CH₃OH 98/2). Two pure factions were collected and theirsolvents were evaporated. The residue was dried, yielding 0.72 g (10%)of (±)-cis-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-[[3fluoro-5-(trifluoromethyl)phenyl]methyl]-4-piperidinyl]-N_(—()2,6-dimethylphenyl)-1-piperazineacetamide(compound 140 ) and 0.88 g (12%) of(±)-trans-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-[[3-fluoro-5-(trifluoro-methyl)phenyl]methyl]-4-piperidinyl]-N_(—()2,6-dimethylphenyl)-1-piperazineacetamide(compound 141).

Tables 1 to 4 list compounds of formula (I) that wer prepared accordington one or more of the foregoing examples (Ex.).

TABLE 1

Co. Physical data No. Ex. —L (mp = melting point) 1 6 —H (±)-cis 2 6 —H(±)-trans 3 9

(±)-cis; mp 196.9° C. 4 9

(±)-trans 5 5

(±)-cis; mp 94.0° C. 6 5

(±)-trans 7 8

(±)-cis-(E); mp 201.0° C. 8 8

(±)-trans-(E); mp 210.1° C. 9 8

(±)-cis; mp 92.1° C. 10 9

(±)-cis; mp 72.8° C. 11 9

(±)-trans 12 9

(±)-cis; mp 100.8° C. 13 9

(±)-trans

TABLE 2

Physical data Co. No. Ex. n p —L (mp = melting point) 14 B.2 1 1 —H(±)-trans 15 B.2 1 1 —H (±)-cis 16 B.1.a 1 1

(±)-cis; mp 143.8° C. 17 B.1.a + b 1 1

(±)-trans; mp 240.3° C.; 1 fumaric acid (1:2) 18 B.1 1 1

(±)-cis; mp 120° C. 19 B.1 1 1

(±)-trans; mp 150° C. 20 B.1 1 1

(±)-cis; mp 70.4° C. 21 B.1 1 1

(±)-trans; mp 169.1° C. 22 B.1 1 1

(±)-trans; mp 173.8° C. 23 B.1 1 1

(±)-cis; mp 93.2° C. 24 B.1 1 1

(±)-trans; mp 100.1° C. 25 B.1 1 1

(±)-trans; mp 75.4° C. 26 B.1 and B.3 1 1

(−)-(A)-trans; mp 97.4° C.; [α]_(D) ²⁰ = −5.81° (c = 1% in DMF) 27 B.1and B.3 1 1

(−)-(B)-trans; mp 96.8° C.; [α]_(D) ²⁰ = +5.71° (c = 1% in DMF) 28 B.1 11

(±)-cis; (E) 29 B.1 1 1

(±)-trans; (E) 30 B.1 1 1

(±)-trans; mp 185.7° C. 31 B.1 1 1

(±)-cis; mp 77.5° C. 32 B.1 1 1

(±)-cis; mp 183.1° C. 33 B.1 1 1

(±)-trans; mp 115.6° C. 34 B.1 1 2

(±)-trans; mp 120.1° C. 35 B.1 1 1

(±)-cis; mp 150.9° C. 36 B.1 1 1

(±)-trans; mp 120.8° C. 37 B.4 1 1

(±)-cis; mp 85.6° C. 38 B.4 1 1

(±)-trans; mp. 170.5° C. 39 B.4 1 1 —CH₂—CH₂—OH (±)-cis; mp 192.9° C. 40B.4 1 1

(±)-trans; mp 240.7° C. 41 B.4 1 1

(+)-(A)-cis; mp 177.3° C.; [α]_(D) ²⁰ = +19:88° (c = 1% in methanol) 42B.4 1 1

(−)-(B)-cis; mp 177.3° C.; [α]_(D) ²⁰ = −20.34° (c = 1% in methanol) 43B.4 1 1

(±)-cis; mp 88.1° C. 44 B.4 1 1

(±)-cis; mp 227.1° C.; fumaric acid (1:2) 45 B.4 1 1

(±)-trans; mp 200.2° C. 46 B.4 1 1

(±)-trans; mp 105.6° C. 47 B.4 1 1

(±)-cis; mp 89.2° C. 48 B.1 1 1

(±)-trans; mp 89.7° C. 49 B.1 1 1

(±)-cis; mp 135.8° C. 50 B.4 1 1

(±)-trans; mp 140.4° C. 51 B.4 1 1

(±)-cis; mp 173.5° C. 52 B.4 1 1

(±)-cis; mp 101.5° C. 53 B.4 1 1

(±)-trans; mp 185.8° C. 54 B.5 1 1

(±)-cis; mp 260° C. 55 B.5 1 1

(±)-trans; mp 75.2° C. 56 B.5 1 1

(±)-trans; mp 80.1° C. 57 B.5 1 1

(±)-cis 58 B.1 1 1

(±) 59 B.4 1 1

(±)-cis, mp 106.4° C. 60 B.6 1 1

(±)-cis 61 B.6 1 1

(±)-cis 62 B.1 1 1

(±)-cis 63 B.1 1 2

(±)-cis; fumaric acid (1:2) 64 B.2 1 2 —H (±)-cis 65 B.4 1 2

(±)-cis 66 B.1 1 1

(±)-cis 67 B.1 1 1

(±)-trans 68 B.1 1 2

(±)-trans; fumaric acid (1:2) 69 B.4 1 1

(±)-trans 70 B.7 1 1

(±)-cis 71 B.4 1 1

(±)-cis 72 B.4 1 1

(±)-cis 73 B.4 1 1

(±)-cis; fumaric acid (1:2) 74 B.4 1 1

(±)-cis 75 B.4 1 1

(±)-cis; fumaric acid (1:1) 76 B.4 1 1 —CH₂—C(═O)—NH—CH(CH₃)₂ (±)-cis 77B.4 1 2 —H (±)-trans 78 B.4 1 2

(±)-trans 79 B.8 1 1

(±)-cis 80 B.1 1 1

(±)-(B)-trans 81 B.2 1 1 —H (±)-(B)-trans 82 B.1 1 1

(±)-cis 83 B.1 1 1

(±)-trans 84 B.4 1 1

(±)-cis 85 B.7 1 1

(±)-trans 86 B.6 1 1

(±)-trans 87 B.1 1 1

(±)-trans 88 B.1 1 1

(±)-cis; fumaric acid (1:2) 89 B.4 1 1 —(CH₂)₂—OH (±)-trans 90 B.11 1 1

(±)-trans; fumaric acid (1:2) 91 B.4 1 1

(±)-trans; fumaric acid (1:2) 92 B.11 1 1

(±)-trans 93 B.11 1 1

(±)-cis; fumaric acid (1:2) 94 B.4 1 1

(±)-trans 95 1 1

(B)-trans; (L)-malic acid (1:1) 96 B.4 1 1

(±)-trans; fumaric acid (1:2) 97 B.4 1 1

(±)-trans 98 B.4 1 1

(±)-cis 99 B.4 1 1

(±)-cis 100 B.4 1 1

(±)-cis 101 B.4 1 1

(±)-cis 102 B.4 1 1

(±)-cis 103 B.4 1 1

(±)-cis fumaric acid (1:2) 104 B.4 1 1

(±)-trans 105 B.4 1 1

(±)-trans 106 B.4 1 1

(±)-trans 107 B.4 1 1

(±)-trans 108 B.4 1 1

(±)-trans 109 B.4 1 1

(±)-trans 110 B.14 1 1

(±)-trans; fumaric acid (1:2) 111 B.14 1 1

(±)-cis; fumaric acid (1:2) 112 B.4 1 1

(±)-trans 113 B.1 1 1

(±)-trans 114 B.2 1 1 H (±)-trans; fumaric acid (1:2) 115 B.8 1 1

(±)-trans 116 B.8 1 1

(±)-cis 117 B.8 1 1

(±)-trans 118 B.4 1 1

(±)-trans; fumaric acid (1:2) 119 B.4 1 1

(±)-trans 120 B.13 1 1

(±)-trans 121 B.1 1 1

(±)-cis 122 B.1 1 1

(±)-trans 123 B.4 1 1

(±)-cis 124 B.15 1 1

(B)-trans; benzoate (1:1) 125 B.15 1 1

(B)-trans; maleic acid (1:1) 126 B.15 1 1

(B)-trans; hydrochloric acid (1:2) hydrate (1:1) 127 B.15 1 1

(B)-trans; succinic acid (1:1) 128 B.15 1 1

(B)-trans; fumaric acid (1:1) 129 B.9 1 1

(±)-cis; fumaric acid (1:2) 130 B.10 1 1 —CH₃ (±)-cis; fumaric acid(1:2) 131 B.16 0 1

(±)-cis

TABLE 3

Co. No. Ex. X^(&) R² R_(a) R_(b) R_(c) Physical data 132 B.12 c.b.3,5-di(trifluoromethyl)phenyl F H F (±)-cis 133 B.12 c.b.3,5-di(trifluoromethyl)phenyl F H F (±)-trans 134 B.12 c.b.3,5-di(trifluoromethyl)phenyl H F F (±)-cis 135 B.12 c.b.3,5-di(trifluoromethyl)phenyl H F F (±)-trans 136 B.4  c.b.3,5-di(trifluoromethyl)phenyl H CF₃ H (±)-(B) fumaric 137 B.4  c.b.3,5-di(trifluoromethyl)phenyl H CF₃ H (±)-(A) 138 B.13 c.b.3,5-di(trifluoromethyl)phenyl H Cl Cl (±)-cis 139 B.13 c.b.3,5-di(trifluoromethyl)phenyl H Cl Cl (±)-trans 140 B.19 c.b.3,5-di(trifluoromethyl)phenyl F H CF₃ (±)-cis 141 B.19 c.b.3,5-di(trifluoromethyl)phenyl F H CF₃ (±)-trans 142 B.13 c.b.3-isopropoxyphenyl H H H (±)-cis 143 B.18 —NH—3,5-di(trifluoromethyl)phenyl H H H (±)-trans 144 B.13 c.b. phenyl H H H(±)-cis 145 B.13 c.b. 2-naphtyl H H H (±)-trans 146 B.13 c.b.2-quinolinyl H H H (±)-trans 147 B.13 c.b. 2-quinoxalinyl H H H(±)-trans 148 B.13 —O— benzyl H H H (±)-trans 149 B.17 c.b.3-methylbenzofuran-2-yl H H H (±)-trans 150 B.17 c.b.5-fluoro-indol-2-yl H H H (±)-trans 151 B.17 c.b. 5-indolyl H H H(±)-trans 152 B.17 c.b. 5-methyl-pyrazin-2-yl H H H (±)-trans 153 B.13c.b. phenyl H H H (±)-trans 154 B.13 c.b. 5-methyl-isoxazol-3-yl H H H(±)-trans 155 B.13 c.b. 2,4,6-trimethylphenyl H H H (±)-cis 156 B.13c.b. 3,4,5-trimethoxyphenyl H H H (±)-cis 157 B.13 c.b. 3-cyanophenyl HH H (±)-cis 158 B.13 c.b.

H H H (±)-cis 159 B.13 c.b. 3,5-difluorophenyl H H H (±)-cis 160 B.13c.b. 2,6-dichloro-pyridin-4-yl H H H (±)-cis 161 B.13 c.b. 2-naphtyl H HH (±)-cis 162 B.13 c.b. 2-quinolinyl H H H (±)-cis 163 B.13 c.b.3-isopropoxybenzyl H H H (±)-cis 164 B.13 c.b. 1-phenylethyl H H H(±)-cis 165 B.13 c.b. 3-isopropoxyphenyl H H H (±)-trans 166 B.13 c.b.3-cyanophenyl H H H (±)-trans 167 B.13 c.b.

H H H (±)-trans 168 B.13 c.b. 2,4-dichlorophenyl H H H (±)-trans 169B.13 c.b. 2-thienyl H H H (±)-trans ^(&)c.b. = covalent bond

TABLE 4

Co. No. Ex. R_(a) X^(&) R² L Physical data 170 B.1  CF₃ c.b.3,5-di(trifluoro-methyl)phenyl H (±)-(A) 171 B.1  CF₃ c.b.3,5-di(trifluoro-methyl)phenyl H (±)-(B) fumaric acid (1:4) 172 B.13 Hc.b. 3-trifluoromethyl-phenyl benzyl (±)-cis 173 B.13 H c.b.3,5-difluoro-phenyl benzyl (±)-cis 174 B.13 H c.b. 2-naphtyl benzyl(±)-cis 175 B.13 H c.b. 3-cyano-phenyl benzyl (±)-cis 176 B.13 H —O—benzyl benzyl (±)-cis 177 B.13 H c.b. 2-furanyl benzyl (±)-cis 178 B.13H c.b. 2-thienyl benzyl (±)-cis 179 B.13 H c.b. phenyl benzyl (±)-cis180 B.13 H c.b. 3,5-dichloro-phenyl benzyl (±)-cis 181 B.17 H c.b.3,4-dichlorophenyl benzyl (±)-cis 182 B.13 H c.b.

benzyl (±)-cis 183 B.13 H c.b. phenyl benzyl (±)-trans 184 B.13 H c.b.2,6-dichloro-pyridin-4-yl benzyl (±)-trans 185 B.13 H c.b. 2-furanylbenzyl (±)-trans 186 B.13 H c.b. 2-thienyl benzyl (±)-trans 187 B.13 Hc.b. 3-cyano-phenyl benzyl (±)-trans 188 B.13 H c.b.

benzyl (±)-trans 189 B.13 H c.b.

benzyl (±)-trans 190 B.13 H c.b. 5-methyl-isoxazol-3-yl benzyl (±)-trans191 B.13 H c.b. 2-nitrophenyl benzyl (±)-cis 192 B.16 H c.b.2-aminophenyl benzyl (±)-cis fumaric acid (1:2) ^(&)c.b. = covalent bond

TABLE 5 Co. C H N No. Exp Theor Exp Theor Exp Theor 5 75.47 76.05 8.068.02 9.91 10.14 6 75.08 76.05 8.18 8.02 10.02 10.14 7 68.40 68.18 6.686.68 5.52 5.68 8 67.39 68.18 6.83 6.68 5.62 5.68 9 71.98 71.77 7.59 7.407.11 7.17 10 76.99 77.23 8.12 7.90 8.16 8.44 12 81.31 81.83 7.79 7.777.36 7.53 16 64.88 65.19 5.53 5.64 7.05 7.13 17 58.45 58.46 4.85 5.035.01 5.11 19 61.61 61.91 5.03 5.35 10.32 10.62 20 60.51 60.71 4.92 4.926.89 7.08 21 60.74 60.71 4.86 4.92 7.02 7.08 22 63.09 62.87 5.56 5.7210.08 10.18 23 62.68 62.98 5.21 5.28 11.43 11.60 24 62.44 62.98 5.185.28 11.33 11.60 25 60.33 61.53 5.42 5.74 11.62 11.96 26 63.42 63.635.96 5.80 8.52 8.48 27 63.41 63.63 5.82 5.80 8.04 8.48 30 63.02 62.945.19 5.28 7.01 7.10 31 62.68 62.94 5.31 5.28 7.08 7.10 32 66.40 66.475.44 5.58 7.66 7.75 33 66.42 66.47 5.60 5.58 7.55 7.75 34 62.07 62.985.10 5.28 11.46 11.60 35 65.11 65.04 5.08 5.03 5.89 5.99 36 64.94 65.044.97 5.03 6.03 5.99 37 62.58 62.65 5.26 5.42 8.63 8.86 38 60.87 61.625.22 5.48 8.23 8.45 40 62.28 62.43 4.78 5.08 11.28 11.38 41 63.44 63.635.69 5.80 8.36 8.48 42 63.83 63.63 5.77 5.80 8.40 8.48 43 66.54 66.755.52 5.60 5.61 5.70 45 56.47 56.50 4.40 4.60 7.89 7.99 46 64.49 64.715.77 5.87 7.92 8.16 47 63.46 63.63 5.84 5.80 8.39 8.48 48 65.16 65.536.38 6.20 7.71 7.84 49 65.43 65.53 6.25 6.20 7.81 7.84 50 63.71 63.635.64 5.80 8.40 8.48 51 61.79 61.62 5.46 5.48 8.31 8.45 52 64.50 64.715.70 5.87 7.92 8.16 53 63.77 63.63 5.90 5.80 8.25 8.48 54 63.54 64.535.15 5.29 5.19 5.37 55 67.97 68.56 5.65 5.60 6.02 6.31 56 63.34 63.465.39 5.49 6.79 6.94 57 63.54 63.46 5.43 5.49 6.97 6.94 59 63.58 63.635.75 5.80 8.37 8.48 60 64.13 63.97 5.61 5.69 6.60 6.78 61 63.41 63.975.65 5.69 6.60 6.78 62 62.65 62.87 5.76 5.72 9.97 10.18 63 58.77 58.925.14 5.19 4.99 5.03 65 63.78 64.08 6.24 5.98 7.97 8.30 66 62.89 64.225.41 5.39 11.03 10.96 67 63.06 64.22 5.18 5.39 10.62 10.96 69 60.7461.28 5.57 5.68 11.15 11.28 70 62.34 62.53 4.81 5.11 11.62 11.82 7154.59 54.69 4.03 4.20 7.04 7.29 72 59.45 59.57 5.01 5.28 9.71 9.92 7454.84 54.85 4.18 4.47 9.28 9.41 76 59.66 60.19 6.21 6.06 8.93 9.36 7863.95 64.08 5.90 5.98 8.23 8.30 79 55.18 55.25 4.08 4.38 7.04 7.16 8262.65 63.63 5.80 5.80 8.22 8.48 83 61.84 63.63 5.91 5.80 8.00 8.48 8458.20 58.49 5.21 5.38 12.81 13.20 85 61.55 62.53 5.15 5.11 11.53 11.8286 63.82 63.97 5.58 5.69 6.73 6.78 87 67.38 68.37 5.48 6.15 5.48 5.70 9261.87 61.95 5.17 5.32 6.32 6.72 93 57.14 57.47 4.71 4.92 5.02 5.26 9466.62 66.84 5.55 5.75 7.23 7.60 95 58.94 58.94 5.60 5.58 6.97 7.05 9652.25 52.35 4.82 4.97 11.15 11.25 97 62.54 62.35 5.26 5.37 11.64 11.7998 63.86 63.82 5.30 5.51 8.39 8.51 99 64.29 64.28 5.40 5.69 8.17 8.33100 62.13 62.35 5.16 5.37 11.59 11.79 101 64.49 64.28 5.68 5.69 8.088.33 102 67.17 66.84 5.82 5.75 7.36 7.60 103 58.42 58.69 5.39 5.47 6.156.08 104 64.16 64.28 5.73 5.69 8.31 8.33 105 63.95 64.08 6.01 5.98 8.258.30 106 62.27 62.65 5.37 5.42 8.84 8.86 107 63.76 63.82 5.54 5.51 8.458.51 108 54.46 54.69 4.08 4.20 7.20 7.29 109 58.46 58.49 5.19 5.38 12.9013.20 110 56.57 57.14 4.58 4.80 7.96 8.13 111 56.80 57.14 4.59 4.80 7.998.13 112 56.42 56.33 4.73 4.88 10.77 10.95 114 54.52 54.17 4.61 4.825.75 5.74 115 64.06 64.08 6.07 5.98 8.16 8.30 116 63.87 64.08 5.89 5.988.11 8.30 117 55.13 55.25 4.18 4.38 7.05 7.16 118 57.96 58.41 4.90 5.126.06 6.19 119 60.60 60.60 5.45 5.42 9.12 9.42 120 59.92 59.72 4.73 4.706.20 6.53 121 63.51 63.82 5.60 5.51 8.43 8.51 122 63.53 63.82 5.77 5.519.05 8.51 123 64.81 65.00 5.75 5.75 10.17 10.24 131 63.23 63.15 5.725.61 8.51 8.66 132 60.00 60.34 4.90 5.21 7.76 8.04 133 59.93 60.34 5.175.21 7.94 8.04 134 60.22 60.34 5.22 5.21 7.94 8.04 135 60.87 60.34 5.445.21 7.97 8.04 137 59.04 59.34 5.01 5.12 7.43 7.69 138 57.81 57.62 4.764.97 7.54 7.68 139 57.28 57.62 4.73 4.97 7.25 7.68 140 57.53 57.91 4.884.86 7.18 7.50 141 57.45 57.91 4.79 4.86 7.21 7.50 142 73.32 74.19 8.257.96 9.28 9.61 143 61.66 62.21 5.77 5.82 10.21 10.36 144 75.31 75.547.76 7.68 10.28 10.68 145 76.49 77.32 7.43 7.37 9.33 9.75 170 53.7355.03 4.46 4.62 7.14 7.40 192 64.48 65.13 6.20 6.33 7.84 7.99

C. Pharmacological example Example C.1 Antagonism of substance-P inducedrelaxation of the pig coronary arteries

Segments of coronary artieries taken from pigs (killed by injection ofan overdose of sodium pentobarbital) were inverted and mounted forrecordign of isometric tension in organ baths (volume 20 ml) with theendothelium at the outside. The preparations were bathed inKrebs-Henseleit solution. The solution was kept at 37° C. and gassedwith a mixture of O₂/CO₂ (95/5). After stabilisation of thepreparations, prostaglandin F_(2a) (10⁻⁵ M) was administered to induce acontraction. This was repeated until contractivle responses becamestable. Then prostaglandin F_(2a) was again administered and substanceP(3×10⁻¹⁰ M and 10⁻⁹ M cumulatively) was added. Substance P inducedendothelium dependent relaxations. After washing away the agonists, aknown concentratin of a compound of formula (I) was added. After anincubation period of 30 minutes, prostaglandin F_(2a) (10⁵ M) and thesame concentrations of sbustance P as described above were againadministered in the presence of the compound to be tested. Relaxationscaused by substance P were expressed as relaxations under controlconditions, and percent inhibition of the response to 10⁹ M substance Pwas taken as a measure of the antagonistic activity of the compound tobe tested. Table 6 lists the IC₅₀ values (concentration at which 50% ofthe response to 10⁹ M substance P was inhibited by the test compound)for the tested compounds.

TABLE 6 IC₅₀ Co. No. (in 10⁻⁹ M) 5 4.61 17 1.68 19 0.54 22 0.37 24 0.6425 0.79 26 2.75 27 0.13 28 13.3 29 0.45 33 0.60 34 0.35 35 17.0 36 2.3137 9.60 38 0.86 42 0.93 43 5.63 44 8.34 45 0.15 46 0.42 48 0.26 49 0.5950 2.43 51 1.35 52 1.10 53 0.35 55 2.8 56 3.25 58 0.24 59 1.20 61 15.262 0.24 63 8.38 65 6.39 68 5.88 69 1.57 70 0.29 73 5.73 76 14.1 85 0.1586 2.13 87 1.90 91 0.07 92 0.78 93 4.99 94 0.42 95 0.10 97 1.58 99 1.46101 0.75 102 1.85 104 0.30 105 1.05 107 0.96 115 2.23 119 2.81 120 0.82121 2.77 122 1.68 124 0.06 128 0.35 132 2.08 133 0.62 134 0.04 135 0.01136 0.31 137 0.23 138 0.16 139 0.13

Example C.2 Antagonism of substance P induced plasma extravasation inguinea-pigs

Plasma extravasation was induced by injection of substance P (2 mg/kg)in the femoral artery of female guinea-pigs. Evans Blue dye (30 mg/kg)was injected simultaneously. The test compound or solvent wasadministered 1 hour prior to substance P injection. 10 minutes afterchallenge, the aminals were checked for blue colouring (a direct measurefor plasma extravasation) of the nose, the forepaws, and the conjectiva.30 minutes after challenge, the animals were sacrificed by CO₂ gasinhalation and checked for blue colouring of the trachea and the urinarybladder. Doses which actively inhibit substance P-induced plasmaextravasation are defined as thoses doses at which only ⅓ or less of thetotal surface area of the nose, forepaws, conjunctiva, trachea orurinary bladder are coloured blue by an intensive extravastion. Table 7lists the lowest active doses (LAD) in mg/kg for the tested compounds.

TABLE 7 LAD in (mg/kg) Co. No. nose forepaws conjunctiva trachea urinarybladder 8 10.0 10.0 10.0 >40 >40 12 >40.0 >40.0 >40.0 >40 40.0 16 40.040.0 40.0 >40 >40 17 10.0 10.0 10.0 >40 10.0 19 2.50 2.50 2.50 10.0 >4021 10.0 10.0 10.0 >40 10.0 22 2.50 2.50 2.50 10.0 >40 23 10.0 10.040.0 >40 >40 24 2.50 2.50 10.0 10.0 >40 25 2.50 2.50 10.0 >40 >40 2610.0 10.0 20.0 40.0 20.0 27 0.63 0.63 0.63 0.63 0.63 33 2.50 10.02.50 >40 >40 34 2.50 10.0 2.50 10.0 10.0 38 10.0 10.0 10.0 >40 >40 4010.0 10.0 10.0 >40 >40 42 1.25 1.25 2.50 5.00 5.00 45 0.63 0.63 0.63 >402.50 46 0.63 0.63 0.63 >40 0.63 47 40.0 40.0 40.0 >40 >40 48 2.50 2.502.50 2.50 2.50 49 2.50 2.50 2.50 10.0 >40 50 10.0 10.0 10.0 10.0 >40 520.63 0.63 2.50 10.0 10.0 53 1.25 1.25 1.25 2.50 2.50 56 10.0 10.0 10.040.0 2.50 59 2.50 2.50 2.50 5.00 5.00 68 10.0 10.0 40.0 >40 >40 70 10.010.0 10.0 10.0 10.0 73 10.0 10.0 10.0 >40 >40 74 10.0 10.0 10.0 >40 >4082 2.50 2.50 2.50 10.0 >40 83 0.63 0.63 2.50 >40 0.63 85 2.50 2.50 2.502.50 10.0 87 10.0 10.0 10.0 10.0 >40 90 10.0 10.0 10.0 10.0 >40 94 2.502.50 2.50 10.0 10.0 95 0.31 0.31 0.31 0.63 2.50 96 10.0 10.010.0 >40 >40 101 10.0 10.0 10.0 >40 >40 103 2.50 2.50 2.50 10.0 2.50 1052.50 2.50 2.50 >40 >40 107 2.50 2.50 2.50 2.50 10.0 119 2.50 2.50 2.5010.0 >40 128 0.63 0.63 0.63 >40 10.0 132 10.0 10.0 10.0 10.0 10.0 1332.50 2.50 2.50 10.0 10.0 134 10.0 10.0 10.0 10.0 10.0 135 0.63 0.63 0.632.50 >40 136 2.50 2.50 2.50 2.50 2.50 137 2.50 2.50 2.50 2.50 2.50 1382.50 2.50 2.50 10.0 >40 139 2.50 2.50 2.50 2.50 2.50

D. Composition examples

“Active ingredient” (A.I) as used throughout these examples relates to aocmpound of formula (I) a pharmaceutically acceptable addition salt, astereochemically isomeric form thereof or a N-oxide form thereof.

Example D.1 ORAL DROPS

500 Grams of the A.I. was dissolved in 0.51 of 2-hydroxypropanoic acidand 1.51 of the polyethylene glycol at 60˜80° C. After cooling to 30˜40°C. there were added 351 of polyethylene glycol and the emixture wastirred well. Then there was added a solution of 1750 grams of sodiumsaccharin in 2.51 of purified water ans while stirring there were added2.51 of cocoa flavor and polyethylene glycol q.s. to a volume of 501,providing an oral drop solution comprisng 10 mg/ml of A.I. The resultingsolution was filled into suitable containers.

Example D.2 ORAL SOLUTION

9 Grams of methy 4-hydroxybenzoate and 1 gram of propyl4-hydroxybenzoate were dissovled in 41 of boiling purified water. In 31this solution were dissolved first 10 grams of 2,3-dihydroxybutanedioicacid and thereafter 20 grams of the A.I. The latter solution wascombined with the remaining part of the former solution and121,1,2,3-propanetriol and 31 of of sorbital 70% solution were addedthereto. 40 Grams of sodium saccharin were dissolved in 0.51 og waterand 2 ml of rapbery and 2 ml of gooseberry essence were added. Thelatter solution was combined with the former, water was added q.s. to avolume of 201 providng an oral solution comprinsg 5 mg of the activeingredient per teaspoonful (5 ml). The resulting solution was filled insuitable containers.

Example D.3 FILM-COATED TABLETS

Preparation of tablet core

A mixture of 100 grams of the A.I., 570 grams lactose and 200 gramsstarch was mixed well and thereafter humidified with a solution of 5grams sodium dodecyl sulfate and 10 grams polyvinylpyrrolidone in about200 ml of water. The wet powder mixture was sieved, dried and sievedagain. Then there was added 100 grams microcrystalline cellulose and 15grams hydrogenated vegetable oil The whole was mixed well and compressedinto tablets, giving 10,000 tablets, each containing 10 mg of the activeingredient.

Coating

To a solution of 10 grams methyl cellulose in 75 ml o fdenaturatedethanol there was added a solution of 5 grams of ethyl cellulose n 150ml of dichloromethane. Then there were added 75 ml of dichloromethaneand 2.5 ml 1,2,3-propanetriol. 10 Grams of polyethylene glycol wasmolten and dissolved in 75 ml of dichloromethane. The latter solutionwas added to the former and then there were added 2.5 grams of magnesiumoctadecanoate, 5 grams of polyvinylpyrrolidone and 30 ml of concentratedcolour suspension and the whole was homogenated. The tablet cores werecoated with the thus obtained mixture in a coating apparatus.

Example D.4 INJECTABLE SOLUTION

1.8 Grams methyl 4-hydroxybenzoate and 0.2 grams propyl4-hydroxybenzoate were dissolved in abut 0.51 of boiling water forinjection. After cooling to about 50 ° C. there were added whilestirring 4 grams lactic acid, 0.05 grams propylene glycol and 4 grams ofthe A.I. The solution was colled to room temperature and supplementedwith water for injection q.s. ad 1 , giving a solution comprising 4mg/ml of A.I. The solution was sterilized by filtration and filled insterile container.

What is claimed:
 1. A compound selected from the group consisting of:4-[1-[3,5bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6dimethylphenyl)-1-piperazineacetamide; 4-[1-[3,5bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(1-phenylcyclohexyl)-1-piperazineacetamide; 1-[3,5-bis(trifluoromethyl)benzoyl-2-(phenylmethyl)-4-piperidinyl]-N-(1-phenylcyclohexyl)-1-piperazineacetamide;1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-[1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-yl]-1-piperazinyl]-2-(phenylmethyl)piperidine;4-[3,5-bis(trifluoromethyl)benzoyl]-2-[(4-trifluoromethylphenyl)methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide; and4-[3,5-bis(trifluoromethyl)benzoyl]-2-[(3,4-dichlorophenyl)methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazine acetamide; ora N-oxide form, a pharmaceutically acceptable addition salt or astereochemically isomeric form thereof.
 2. A compound as claimed inclaim 1, wherein the compound is(±)-(B)-trans-4-[1-[3,5-bis(trifluoromethyl)benzoyl;]-2-(phenylmethy)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide; (−)-(B)cis-4-[1-[3,5-bis(trifluoromethyl)benzoly]-2-(phenylmethy)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide; or (±)-(B)-trans-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide, (L)-malic acid (1:1).
 3. A composition comprising apharmaceutically acceptable carrier, and as active ingredient atherapeutically effective amount of a compound as claimed in claim
 1. 4.A process of preparing a composition as claimed in claim 3,characterized in that the pharmaceutically acceptable carrier isintimately mixed with a therapeutically effective amount of thecompound.